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REMOTE  5  ORAGE 

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CLINICAL  HEMATOLOGY. 

DaCOSTA. 


Digitized  by  the  Internet  Archive 
in  2015 


https://archive.org/details/clinicalhematoloOOdaco_0 


tmkm 


The  Leucocytes. 
(Wright's  Stain.) 

I.  Normal  erythrocytes. 
II.  Large  and  small  lymphocytes  and  transitional  forms. 

III.  Polynuclear  neutrophil es. 

IV.  Blood  plaques. 
V.  Eosinophiles 

VI.  Myelocytes. 
VII.  Mast  cells. 

(E.  F.  Faber,  fee.) 


CLINICAL 

HEMATOLOGY 


A  PRACTICAL  GUIDE  TO  THE 
EXAMINATION  OF  THE  BLOOD 
WITH  REFERENCE  TO  DIAGNOSIS 


BY 

v 

JOHN  C.  DaCOSTA,  Jr.,  M.D. 

DEMONSTRATOR    OF    CLINICAL    MEDICINE,    JEFFERSON    MEDICAL    COLLEGE;    CHIEF    OF  MEDICAL 
CLINIC    AND   ASSISTANT   VISITING    PHYSICIAN,  JEFFERSON    MEDICAL   COLLEGE  HOSPITAL; 
HEMATOLOGIST,  GERMAN  HOSPITAL;    ASSISTANT  VISITING    PHYSICIAN,  PHILADEL- 
PHIA   GENERAL    HOSPITAL  ;    FELLOW    OF    THE    COLLEGE    OF  PHYSICIANS 
OF  PHILADELPHIA 


Second  jEfcition,  IRewsefc  anfc  Bnlargefc 

CONTAINING  NINE  FULL-PAGE  COLORED  PLATES,  THREE  CHARTS, 
AND  SIXTY-FOUR  OTHER  ILLUSTRATIONS 


PHILADELPHIA 

P.  BLAKISTON'S  SON  &  CO. 

1012  WALNUT  STREET 
1907 


Copyright,  1904,  by  P.  Blakiston's  Son  &  Co. 
Registered  at  Stationers'  Hall,  London,  England 


PRESS  OF 
WM.   F.   FELL  COMPANY 
PHILADELPHIA 


PREFACE  TO  THE  SECOND  EDITION. 


Three  noteworthy  lines  of  advance  have  developed  from  recent 
work  in  hematology:  the  identification  of  new  clinical  entities, 
the  correlation  of  blood  pictures  with  a  number  of  diseases  hitherto 
unstudied  or  imperfectly  investigated  hematological^,  and  the 
proof  of  the  septic  nature  of  many  of  the  specific  infections.  The 
first  has  established  upon  a  clinical  basis  trypanosomiasis,  kala-azar, 
spotted  (Montana)  fever,  and  cyanotic  polycythemia;  the  second 
has  shown  in  detail  the  blood  changes  incident  to  chloroma,  hydatid 
infection,  multiple  periostitis,  pancreatitis,  variola,  arthritis  defor- 
mans, sprue,  leukanemia,  burns,  and  x-ray  therapy;  and  the  last 
has  proved  the  bacteriemic  character  of  enteric  fever,  Malta  fever, 
pneumonia,  scarlet  fever,  and,  possibly,  rheumatic  fever.  Prog- 
ress of  great  practical  value  has  been  made  in  the  technic  of 
blood  examinations,  notably  in  staining  methods,  in  serum  diag- 
nosis, and  in  blood  culturing.  These  advances,  all  made  during 
the  past  two  years,  have  been  incorporated  in  this  edition,  together 
with  much  other  new  material,  gleaned  by  the  consultation  of 
more  than  nine  hundred  late  references  to  hematological  literature. 

The  original  data  of  the  book  are  based  upon  the  records  of 
about  ten  thousand  blood  examinations,  made  chiefly  at  the  Ger- 
man, the  Jefferson,  and  the  Philadelphia  General  Hospitals.  This 
new  matter  relates  more  especially  to  the  primary  anemias,  malig- 
nant disease,  cholelithiasis,  icterus,  pancreatitis,  gastric  ulcer,  pneu- 
monia, septicemia,  and  suppurative  lesions.  For  the  sake  of  clear- 
ness, tabulations  have  been  avoided  as  far  as  possible,  and  the 
data  analyzed  and  presented  as  summaries.  Among  the  improve- 
ments in  technic  described  are  Wright's  stain,  Milian's  method 
of  estimating  the  coagulation  time,  Reudiger's  serum  test,  medico- 
legal tests  for  blood,  and  cryoscopy.  A  brief  account  is  given  of 
Ehrlich's  side-chain  theory  and  its  relation  to  immunity  and  to 
hemolysis.  The  detailed  revision  of  the  text  has  been  supple- 
mented by  the  addition  of  a  new  colored  plate  and  numerous  other 
illustrations. 

In  this  revision  the  plan  of  the  first  edition  has  been  adhered 
to — the  interpretation  of  the  blood  report  as  a  rational  aid  to 

vii 


166629 


viii 


PRKIACK   TO    llll.  SKCONI)  KDITION. 


diagnosis.  The  author  has  profited  by  the  views  of  his  critics 
whenever  they  could  be  consistently  adopted,  and  he  begs  to 
acknowledge  his  appreciation  of  the  many  suggestions  from  this 
source. 

1022  Spruce  Street,  Philadelphia, 
November  i,  1904. 


PREFACE  TO  THE  FIRST  EDITION. 


This  book,  designed  as  a  practical  guide  to  the  examination  of 
the  blood  by  methods  adapted  to  routine  clinical  work,  represents 
an  endeavor  to  recount  the  salient  facts  of  hematology  as  they  are 
understood  at  the  present  time,  to  correlate  certain  of  these  facts 
with  familiar  pictures  of  disease,  and  to  apply  them  to  medical 
and  surgical  diagnosis.  The  purpose  has  been  to  interpret  the 
blood  report  according  to  its  true  value  as  a  clinical  sign,  neither 
exploiting  it  as  a  panacea  for  every  diagnostic  ill,  nor  belittling  it 
because  of  its  failure  consistently  to  give  the  sought-for  clue  in 
every  instance. 

A  minimum  amount  of  theoretical  discussion  has  been  intro- 
duced in  the  sections  dealing  with  the  physiology  and  pathology  of 
the  whole  blood  and  of  the  cellular  elements — only  sufficient,  in  the 
author's  judgment,  to  add  clearness  to  the  number  of  the  mooted 
points  of  this  science,  which  in  its  present  transitional  stage  must 
still  be  regarded  as  one  from  which  more  or  less  hypothesis  and 
conjecture  are  inseparable.  Intimate  familiarity  with  technic 
being  an  essential  qualification  for  the  comprehensive  study  of  the 
blood,  a  somewhat  lengthy  consideration  of  this  subject  is  given. 
The  methods  of  examination  likely  to  prove  useful  in  everyday 
practice  have  been  described  in  detail,  perhaps  somewhat  at  the 
risk  of  prolixity,  in  the  hope  of  thus  simplifying  for  the  novice  the 
minutia?  of  blood  counting,  staining,  and  other  means  of  investi- 
gation. In  the  discussion  of  the  primary  anemias  and  of  the 
anemias  peculiar  to  infancy,  prominent  clinical  features  other  than 
those  referable  to  the  blood  have  been  briefly  mentioned,  in  order 
to  add  clearness  to  the  differential  diagnosis.  For  convenience  in 
reference,  the  various  diseases  included  in  the  section  on  general 
hematology  are  arranged  alphabetically,  rather  than  grouped 
according  to  a  traditional  classification. 

The  greater  part  of  the  original  data  referred  to  in  the  text  is 
taken  from  the  records  of  the  Pathological  Institute  of  the  German 
Hospital,  where  a  systematic  account  of  all  blood  examinations  has 
been  kept  for  the  past  six  years.  The  remaining  data  represent 
the  writer's  personal  examinations  in  hospital  and  private  practice 
and  in  the  Army  Medical  Service,  these  sources  of  statistics 
together  including  about  four  thousand  blood  reports  in  various 
pathological  conditions. 

ix 


X 


I'RKKACK  TO  THK    KIR  ST  KDITION. 


Hematological  Literature  lias  been  freely  consulted  in  the  prepa 
ration  of  this  volume,  special  acknowledgment  being  Hue  to 
Hayem,  Fhrlich  and  Lazarus,  von  Limbeck,  Rieder,  Lowit,  Turk, 
Grawitz,  Cabot,  Stengel3  'Thayer,  Ewing,  Taylor,  and  Coles  for 
the  profitable  information  gleaned  from  their  writings.  Due 
credit  in  the  text  has  been  given  to  these  as  well  as  to  the  other 
authors  of  whose  labors  use  has  been  made. 

The  colored  plates  and  other  histological  illustrations,  the  origi- 
nals of  which  were  made  by  Mr.  E.  F.  Faber  from  fresh  and  stained 
specimens,  bear  evidence  of  the  artist's  technical  skill  and  faithful 
attention  to  structural  detail.  Mr.  S.  Trenner  has  kindly  furnished 
the  engravings  of  several  of  the  special  instruments. 

The  author  takes  pleasure  in  acknowledging  the  assistance  of  his 
wife  and  critic  in  revising  the  proofs  of  these  pages;  in  crediting 
Dr.  G.  P.  Mtiller  for  collecting  and  verifying  much  statistical 
matter  relating  to  hospital  cases;  and  in  thanking  Dr.  J.  Chalmers 
Da  Costa  and  Dr.  T.  G.  Ashton  for  helpful  suggestions. 

313  South  Thirteenth  Street,  Philadelphia, 
November  190 1 


TABLE  OF  CONTENTS. 


INTRODUCTION,  xxxi 

SECTION  I. 

EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

Page 

General  Schema,  -   33 

I.  Microscopical  Examination  of  the  Fresh  Blood,   33 

Obtaining  the  Specimen,   33 

Preparing  the  Slide,   35 

Microscopical  Examination,  -  37 

Changes  Affecting  the  Erythrocytes,   37 

Changes  Affecting  the  Leucocytes,    37 

Increase  in  Fibrin,  Blood  Plaques,  and  Hemoconia,   38 

Blood  Parasites,    39 

Foreign  Bodies,   39 

II.  Estimation  of  the  Percentage  or  Hemoglobin,   39 

Dare's  Hemoglobinometer,   41 

Von  Fleischl's  Hemometer,   43 

Oliver's  Hemoglobinometer,    49 

Gowers' Hemoglobinometer,   5 2 

Haldane's  Hemoglobinometer,  .   53 

Tallquist's  Method,   54 

Haig's  Blood  Decimal  Card,   55 

III.  Counting  the  Erythrocytes  and  the  Leucocytes,   55 

Methods,   55 

Diluting  Fluids,   5.6 

The  Thoma-Zeiss  Hemocytometer,   57 

Counting  the  Erythrocytes,   60 

Counting  the  Leucocytes,   64 

Cleaning  the  Pipette,   67 

Durham's  Hemocytometer,    68 

Gowers'  Hemocytometer,    69 

Oliver's  Hemocytometer,    71 

Dry  Film  Method,   73 

IV.  Microscopical  Examination  of  the  Stained  Specimen,   75 

Objects  of  Staining,   75 

The  Anilin  Dyes,  .   76 

Preparing  the  Films,    76 

Fixation  Methods,    79 

Methods  of  Staining,   •   81 

Wright's  Stain,   82 

Ehrlich's  Triacid  Stain,   83 

Prince's  Stain,   85 

Staining  with  Eosin  and  Methylene-blue,    86 

Staining  with  Eosin  and  Hematoxylin,   87 

Staining  with  Thionin,    87 

Staining  with  Polychrome  Methylene-blue,    88 

Differential  Counting,   89 

xi 


XI] 


TABLE  OE  CONTENTS. 


V.  Counting  thk  Blood  Plaques,   90 

Determann's  Method,   go 

VI.  Estimation  of  the  Relative  Volumes  of  Corpuscles  and  Plasma,  .  9 1 

Daland's  Hematocrit,    91 

Limitations  of  the  Hematocrit,   93 

VII.  Estimation  of  the  Specific  Gravity,   94 

Hammerschlag's  Method,   94 

VIII.  Estimation  of  the  Alkalinity,   96 

Engel's  Alkalimeter,    96 

Dare's  Hemo-alkalimeter,    98 

IX.  Determination  of  the  Rapidity  of  Coagulation,   100 

Glass  Slide  Method,    100 

Wright's  Coagulometer,    101 

X.  Cryoscopical  Examination,   102 

Cryoscopy  in  Pathological  Conditions,    102 

Fontaine's  Cryoscope,   104 

XI.  Estimation  of  the  Resistance  of  the  Erythrocytes,   106 

Hamburger's  Method,   106 

XII.  Spectroscopical  Examination,   107 

The  Sorby-Beck  Microspectroscope,  f   107 

XIII.  Bacteriological  Examination,   109 

Value  of  Positive  Findings,   109 

Methods,   109 

Blood  Cultures,    109 

Staining  Methods,   in 

XIV.  Determination  of  the  Serum  Reaction,   112 

Widal'sTest,    112 

The  Serum  Reaction  in  Specific  Infections,  113 

XV.  Medico-legal  Tests  for  Blood,    114 

Methods,    114 

Microscopical  Examination,   114 

Spectroscopy,     115 

Teichmann' s  Hemin  Test,   115 

The  Guaiacum  Test,   116 

The  Biological  Test,    117 

Hanging  Drop  Test,    122 

Other  Methods  of  Blood  Examination,   122 


SECTION  II. 

THE  BLOOD  AS  A  WHOLE. 


I.  General  Composition,   125 

Plasma,  Serum,  and  Cells,    125 

Salts,   126 

Extractives,   126 

Gases,    126 

II.  Color,   126 

Normal  Variations,    126 

Density  and  Opacity,    126 

Pathological  Variations,    127 

III.  Odor  and  Viscosity,  .   127 


TABLE  OF  CONTENTS.  xiii 

Page 

IV.  Reaction,   128 

Reaction  in  Health,   128 

Table  of  Normal  Blood  Alkalinity,    129 

Physiological  Variations,    129 

Pathological  Variations,   13° 

V.  Specific  Gravity,   132 

Normal  Range,   132 

Pathological  Variations,    132 

Relation  of  Specific  Gravity  to  Hemoglobin,    133 

Table  of  Hemoglobin  Equivalents,    133 

VI.  Fibrin  and  Coagulation,   134 

Relation  of  Fibrin  to  Coagulation,   134 

Appearance  of  Fibrin  in  Fresh  Blood,  1 ,   135 

Hyperinosis  and  Hypinosis,   135 

Pathological  Variations  in  Amount  of  Fibrin,   136 

VII.  Oligemia,   138 

Definition,   138 

Occurrence,    138 

VHI.|Plethora,   138 

Definition,   138 

Permanent  and  Transient  Polyemia,   139 

Serous  Plethora,   139 

Cellular  Plethora,   139 

IX.  Hydremia,   139 

Definition,   139 

Causes,   14° 

Occurrence,    14° 

jX.  Anhydremia,   14° 

Definition,   14° 

Causes,    141 

Occurrence,    141 

XI.  LlPEMIA,   141 

Amount  of  Fat  in  Normal  Blood,   141 

Definition,   14 1 

Physiological  and  Pathological  Lipemia,    142 

Tests  for  Fat,   142 

XII.  Melanemia,   142 

Definition,   142 

Occurrence,   142 

XIII.  Glycemia,   143 

Amount  of  Sugar  in  Normal  Blood,   143 

Hvperglycemia,    143 

Test  for  Sugar,   143 

XIV.  Uric  acidemia,    144 

Definition,   144 

Occurrence,   144 

Test  for  Uric  Acid,   144 

XV.  Cholemia,   145 

Definition,   145 

Occurrence,    145 

Test  for  Bile,    145 


TABLE  OF  CONTENTS. 


XVI.  Acetonemia  and  LlPACIDEMIA,   145 

Definition,   145 

Occurrence,    145 

Tests  for  Acetone  and  Fatty  Acids,    145 

XVII.  Bacteriemia,    146 

Occurrence,    146 

Latent  Infection,    146 

Blood  Cultures,    147 

Bacteria  Found  in  the  Blood,   148 

XVIII.  Anemia,    148 

Definition,   148 

Pseudo-anemia,    149 

Classification,    150 

Pathogenesis,    151 

XIX.  Hemolysis,    151 

Ehrlich's  Side'-chain  Theory,    151 

Hemolysis,    154 

Antihemolysis,    155 

Agglutination  and  Precipitation,    156 


SECTION  III. 

HEMOGLOBIN,  ERYTHROCYTES,  BLOOD  PLAQUES, 
AND  HEMOKONIA. 

I.  Hemoglobin,   161 

General  Properties,   161 

Origin,   162 

Variations  in  Amount,   163 

Absolute  Amount,    165 

Color  Index,    165 

Hemoglobinemia,   166 

Methemoglobinemia,   167 

Carbon  Monoxid  Hemoglobin,    168 

II.  The  Erythrocytes,   169 

Appearance  in  Fresh  Blood,    169 

Histological  Structure,   170 

Origin  and  Life  History,    171 

Size,   172 

Normal  Number,   173 

Volume  Index,   173 

III.  Influence  of  Physiological  Factors  on  the  Erythrocytes,    174 

Age  and  Sex,   174 

Pregnancy,  Menstruation,  and  Lactation,    175 

Constitution  and  Nutrition,    176 

Muscular  Exercise,    176 

Fatigue,    176 

Digestion  and  Food,    177 

High  Altitudes,   178 

Climate,    180 

IV.  Pathological  Changes  in  the  Erythrocytes,    180 

Ameboid  Motility,    180 

Alterations  in  Isotonicity,   180 

Hyperviscosity,   18  r 


TABLE  OF  CONTENTS.  _  XV 

Page 

Deformities  of  Shape  and  Size,   182 

Megalocytes,   182 

Microcytes,    1^>2 

Poikilocytes,    183 

Endoglobular  Degeneration,    184 

Total  Necrosis,   185 

Atypical  Staining  Reaction,   186 

Nucleation,    187 

Normoblasts,   187 

Megaloblasts,    189 

Microblasts,    *92 

Atypical  Erythroblasts,   192 

Ring  Bodies,   *94 

Granular  Basophilia,   194 

Schiiffner's  Granules,   -   196 

Oligocythemia,    196 

Polycythemia,   19  7 

V.  Blood  Plaques,   198 

Appearance  in  Fresh  Blood,    198 

Histological  Structure,    199 

Origin,   199 

Normal  Number,   200 

Pathological  Variations,    200 

VI.  Hemokonia,    200 

Appearance  in  Fresh  Blood,    200 

Histological  Characteristics,   200 

Occurrence,    201 


SECTION  IV. 

THE  LEUCOCYTES. 

I.  General  Characteristics,   205 

Appearance  in  Fresh  Blood,    205 

Ameboid  Movement,  -   206 

Cell  Granules,    207 

Normal  Number,   209 

II.  Classification,    209 

Number  and  Percentage  of  Different  Varieties,   209 

Small  Lymphocytes,    210 

Large  Lymphocytes,   211 

Transitional  Forms,    213 

Polynuclear  Neutrophiles,    214 

Eosinophiles,    216 

Basophiles,    217 

Myelocytes,   217 

Mast  Cells,   219 

Mononuclear  Neutrophiles,    222 

Neutrophilic  Pseudolymphocytes,    222 

Reizungsformen,    222 

Differential  Table  of  the  Leucocytes,    223 

Origin  and  Development,    224 

Iodin  Reaction,    226 

Perinuclear  Basophilia,   228 


\vi 


TABLE  OF  CONTENTS. 


III.  Leucocytosis,   

Definition,   "  22g 

Classification  of  the  Lcucocytoses,   220 

Physiological  Leucocytosis,   ........  220 

Character,   !  2^0 

Causal  Factors,   230 

Leucocytosis  of  the  New-born,  /  [  230 

Digestion  Leucocytosis,             231 

Leucocytosis  of  Pregnancy  and  Parturition,  .  .  ." 

Leucocytosis  Due  to  Thermal  and  M<  <  lianiral  I  nlluenccs,  .  .  .'.  234 

Terminal  Leucocytosis,   2^,- 

Pathological  Leucocytosis,   236 

Occurrence,    '  2_Q 

Degree  of  Increase,   *  /  3,5 

Differential  Changes,             237 

Causal  Factors,    "  2?7 

Functions,   238 

Hypoleucqcytosis  and  Hyperleucocytosis,   239 

Leucocytolysis,   240 

Changes  in  the  Bone  Marrow,   "  ]  ]  241 

-Inflammatory  and  Infectious  Leucocytosis,   242 

Post-operative  Leucocytosis,    244 

Leucocytosis  of  Malignant  Disease,   245 

Post-hemorrhagic  Leucocytosis,    246 

Toxic  Leucocytosis,   247 

Ether  Leucocytosis,   248 

Chloroform  Leucocytosis,   249 

Experimental  Leucocytosis,   249 

IV.  Lymphocytosis,    2?2 

Definition,   *  2~2 

Differential  Changes,   ]"  252 

Causal  Factors,   253 

Physiological  Lymphocytosis,    253 

Pathological  Lymphocytosis,   254 

Experimental  Lymphocytosis,   254 

Clinical  Significance,   254 

V.  Eosinophilia,   255 

Definition,   2^ 

Causal  Factors,    256 

Physiological  Eosinophilia,   2$6 

Pathological  Eosinophilia,    256 

Experimental  Eosinophilia,    257 

Diminution  in  the  Number  of  Eosinophiles,   257 

Clinical  Significance,   258 

VI.  Basophilia,    258 

VII.  Myelemia,   259 

Definition,   259 

Occurrence,    259 

Causal  Factors,   260 

VIII.  Leucopenia,    260 

Definition,   26o 

Differential  Changes,    261 

Physiological  Leucopenia,   . .'   261 

Pathological  Leucopenia,   262 

Experimental  Leucopenia,   262 


TABLE  OF  CONTENTS. 


xvii 


SECTION  V. 

DISEASES  OF  THE  BLOOD. 

Page 

I.  Chlorosis,   ----   207 

Volume,  Oxygen  Capacity,  and  Albumin,    267 

Appearance  of  the  Fresh  Blood,   267 

Coagulation,    268 

Specific  Gravity,    268 

•  Alkalinity,    268 

Hemoglobin  and  Erythrocytes,    269 

Color  Index,    209 

Deformed  and  Nucleated  Erythrocytes,    271 

Leucocytes,    272 

Differential  Changes,    272 

Blood  Plaques,   2  74 

Diagnosis,    2  74 

Clinical  Features,   2  75 

II.  Pernicious  Anemia,    276 

Volume,  Oxygen  Capacity,  and  Albumin,    276 

Appearance  of  the  Fresh  Blood,   276 

Coagulation,   *   277 

Specific  Gravity,   278 

Alkalinity,    278 

Hemoglobin  and  Erythrocytes,    278 

Color  Index,   •--  2  79 

The  Blood  During  Remissions,   280 

Megalocytosis,   281 

Poikilocytosis,   -   281 

Prevalence  of  Megaloblasts,    282 

Polychromatophilia,    285 

Granular  Basophilia,    285 

Leucocytes,      285 

Differential  Changes,    286 

Blood  Plaques,   a87 

Diagnosis,     287 

Clinical  Features,  :   288 

Pernicious  Anemia  and  Severe  Secondary  Anemia,   289 

Pernicious  Anemia  and  Chlorosis,    289 

Pernicious  Anemia  and  Bothriocephalus  Anemia,   290 

Pernicious  Anemia  and  Nitrobenzene  Poisoning,    290 

Conversion  of  Pernicious  Anemia  into  Leukemia,    290 

Leukanemia,    29° 

III.  Splenic  Anemia,    29I 

Appearance  of  the  Fresh  Blood,   291 

Hemoglobin  and  Erythrocytes,   -   29I 

Color  Index,    29* 

Deformed  and  Nucleated  Erythrocytes,    292 

Leucocytes,   -  292 

Blood  Plaques,    293 

Diagnosis,   293 

Clinical  Features,   294 

Splenic  Anemia  and  Myelogenous  Leukemia,    295 

Splenic  Anemia  and  Pernicious  Anemia,   295 

Splenic  Anemia  and  Hodgkin's  Disease,   295 

Splenic  Anemia  and  Splenic  Tumors,    295 

IV.  Secondary  Anemia,    29° 

Appearance  of  the  Fresh  Blood,   296 


Will 


TAHI.K  ()K  CONTKNTS. 


Coagulation,    P<*« 

Specific  Gravity,      J, 

Alkalinity,   \\\ *9j? 

Hemoglobin  and  Erythrocytes,      206 

Color  Index,      y 

Deformed and  Nucleated  Erythrocytes",                          207 

Leucocytes,      jL 

Differential  Changes,    ...              '  3 

Blood  Plaques,   "jY      .  ' 208 

Diagnosis,              \  298 

V.  Post-hemorrhagic  Anemia,   

Etiology,     

Immediate  Effects  of  Hemorrhage,    200 

Secondary  Effects  of  Hemorrhage,   ~o 

Degree  of  Blood  Loss  Compatible  with  Life,   * ,OQ 

Regeneration  of  the  Blood,  ... 

Blood  Crises,  <  ."  ]  [  [[[  \  \  \  \  \  \\  \\\\\\\\\\\\  fQ2 

Differential  Table  of  the  Anemias,   3o3 

VI.  Leukemia,   

Varieties,  \Q2 

Conversion  of  Leukemia  into  Pernicious  Anemia,  304 

Parasitology,  

Myelogenous  Leukemia,  ][ "  ^5 

Appearance  of  the  Fresh  Blood,              306 


Coagulation, 
Alkalinity, 


307 
3°7 


Specific  Gravity,   ...'■„ 

Hemoglobin  and  Erythrocytes,   .......[.  308 

Color  Index,               308 

Relation  of  Erythrocyte  and  Leucocyte  Counts,   308 

Erythroblasts,  " " "  ^„ 

Leucocytes,                   310 

Influence  of  Arsenic  on  the  Leucocyte  Count,    3H 

The  Blood  During  Remissions,   [  ]  3  x  x 

Influence  of  Rontgen-ray  Treatment,             312 

Differential  Changes,    312 

Blood  Plaques,  .......'...[....  317 

Lymphatic  Leukemia,               317 

Appearance  of  the  Fresh  Blood,                       317 

Hemoglobin  and  Erythrocytes,   317 

Deformed  and  Nucleated  Erythrocytes,             318 

Differential  Changes,    *  310 

Blood  Plaques,                        321 

Acute  Leukemia,  ■  '  ^21 

Influence  of  Intercurrent  Infections,   322 

Diagnosis,   323 

Myelogenous  and  Lymphatic  Leukemia,                 325 

Leukemia  and  Pathological  Leucocytosis,    325 

Leukemia  and  Lymphocytosis,   "  325 

Leukemia  and  Hodgkin's  Disease,    326 

Leukemia  and  Chloroma,   326 

Leukemia  and  Multiple  Periostitis,   "  326 

Leukemia  and  Still's  Disease,   326 

Leukemia  and  Tumors  of  the  Spleen,  Kidney,  and  Pancreas,   327 

Leukemia  and  Lymphatic  Hyperplasia,   327 

VII.  Hodgkin's  Disease,    327 

Appearance  of  the  Fresh  Blood,   327 


TABLE  OV  CONTENTS.  XIX 

Page 

Hemoglobin  and  Erythrocytes,    327 

Color  Index,    32& 

Nucleated  and  Deformed  Erythrocytes,    328 

Leucocytes,    32& 

Differential  Changes,   328 

Conversion  of  Hodgkin's  Disease  into  Leukemia,   329 

Diagnosis,    33° 

Clinical  Features,   331 

Influence  of  Rontgen-ray  Treatment,    331 

Hodgkin's  Disease  and  Tuberculous  Adenitis,   331 

Hodgkin's  Disease  and  Syphilitic  Adenitis,    332 

Hodgkin's  Disease  and  Local  Lymphoma,   332 

Hodgkin's  Disease  and  Lymphatic  Sarcoma,   332 

Hodgkin's  Disease  and  Lymphatic  Carcinoma,   333 

VIII.  The  Effect  on  the  Blood  of  Splenectomy,   333 

Hemoglobin  and  Erythrocytes,    333 

Leucocytes,    335 

Differential  Changes,    336 

Factors  of  the  Blood  Changes  Following  Splenectomy,   336 

Differential  Table  of  Leukemia,  Hodgkin's  Disease,  Leucocytosis, 

and  Lymphocytosis   337 

SECTION  VI. 

THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 

I.  Characteristics  of  the  Blood  in  Children,   341 

Fetal  Blood,   -   34 1 

The  Blood  at  Birth,    342 

II.  Anemia  in  Children,    345 

Frequency,   ,   345 

General  Characteristics,   345 

Classification,    346 

Primary  Anemia,    347 

Pernicious  Anemia,   347 

Splenic  Anemia,   347 

Leukemia,   348 

Secondary  Anemia,    351 

Mild  Anemia,   35 1 

Severe  Anemia,    351 

Anemias  with  Leucocytosis,   352 

Etiology  of  Secondary  Anemia,    352 

Anemia  Due  to  Syphilis,   352 

Anemia  Due  to  Rachitis,  —   353 

Anemia  Due  to  Tuberculosis,   353 

Anemia  Due  to  Gastro-intestinal  Diseases,   353 

Post-typhoid  Anemia,   354 

Anemia  Infantum  Pseudoleukemia,    354 

Bacteriemia,    35^ 

SECTION  VII. 

GENERAL  HEMATOLOGY. 

I.  Abscess,  -   36r 

Coagulation,  Fibrin,  and  Iodin  Reaction,   361 

Hemoglobin  and  Erythrocytes,    361 

Factors  of  the  Anemia  in  Abscess,    361 

Cell  Deformity  and  Nucleation,   362 


XX 


TAHI.K  OF  CONTKNTS. 


Page 

Leucocytes   362 

Relation  of  the  Leucocyte  Count  to  the  Local  Lesion,   362 

Range  of  the  Leucocyte  Count  in  Different  Forms  of  Abscess,  .  363 

Differential  Changes,    363 

Diagnosis   363 

II.  Acromegaly,    364 

III.  Actinomycosis,    364 

IV.  Acute  Yellow  Atrophy  of  the  Liver,    365 

V.  Addison's  Disease,   365 

VI.  Anthrax,    366 

VII.  Appendicitis,    ^66 

Factors  of  the  Anemia,    366 

Grade  of  Anemia  in  Catarrhal  and  Suppurative  Cases,   366 

,  Hemoglobin  and  Erythrocytes,    366 

'Cell  Deformity  and  Nucleation,   367 

Leucocytes,   368 

Range  of  the  Leucocyte  Count  in  Different  Forms  of  Appendi- 
citis,   369 

Differential  Changes,   369 

Iodin  Reaction,    370 

Diagnosis,    370 

Clinical  Value  of  the  Blood  Examination,   371 

VIII.  Arthritis  Deformans,   37! 


IX.  Asiatic  Cholera,   ^72 

X.  Asthma  and  Emphysema,   374 

XI.  Bronchitis,    ^75 

XII.  Bubonic  Plague,   3^5 

Coagulation,    3^5 

Bacteriology,   

Serum  Reaction,    ^77 

Hemoglobin  and  Erythrocytes,    377 

Leucocytes,   ,   377 

Blood  Plaques,   378 

XIII.  Burns,    ^78 

XIV.  Chloroma,   :   ^ 

XV.  Cholelithiasis,   380 

Fibrin  and  Coagulation,    380 

Bacteriology,   "  !  ~ 380 

Hemoglobin  and  Erythrocytes,    380 

Leucocytes,    381 

Diagnosis,    381 

XVI.  Cyanotic  Polycythemia,   381 

XVII.  Dengue,    382 

XVIII.*DlABETES  MELLITUS,   383 

Alkalinity,  Lipemia,  Lipacidemia,  and  Glycemia,   383 

Williamson's  Test,   383 

Bremer's  Test,   384 

Hemoglobin  and  Erythrocytes,    385 

Leucocytes,    386 

Digestion  Leucocytosis,    386 

Iodin  Reaction,   386 

Diagnosis,    386 


TABLE  OF  CONTENTS. 


xxi 


Page 

XIX.  Diphtheria,    386 

Hemoglobin  and  Erythrocytes,    386 

Leucocytes,    387 

Course  of  the  Leucocytosis,    388 

Influence  of  Antitoxin  on  the  Leucocyte  Count,   388 

Differential  Changes,    388 

Affinity  of  the  Leucocytes  for  Basic  Dyes,   389 

Diagnosis,    390 

XX.  Enteritis,    390 

Enteritis,  Diarrhea,  and  Gastro-enteritis,   390 

Dysentery  and  Ulcerative  Enteritis,   391 

Effect  of  Purges,   392 

XXI.  Enteric  Fever,   393 

Alkalinity  and  Coagulation,   393 

Bacteriology,   393 

Blood  Cultures,    393 

Spot  Cultures,    395 

Serum  Reaction,    396 

Dried  Blood  Method,   398 

Fluid  Blood  Method,   399 

Macroscopical  Method,    400 

The  Test  with  Dead  Cultures,    401 

The  Choice  of  a  Method,    401 

Value  of  the  Serum  Test,   402 

Positive  Reactions  in  Non-typhoid  Conditions,    403 

Hemoglobin  and  Erythrocytes,    404 

Cell  Deformity  and  Nucleation,   406 

Leucocytes,   406 

Differential  Changes,    408 

Effect  of  Complications,    408 

Blood  Plaques,   409 

Diagnosis,    409 

XXII.  Erysipelas,   41° 

XXIII.  Exophthalmic  Goiter,   411 

XXIV.  Fever,    411 

Factors  of  the  Blood  Changes,    412 

Pyrexial  Polycythemia  and  Post-febrile  Anemia,   412 

Coagulation,  Fibrin,  and  Alkalinity,   412 

The  Leucocytes,   412 

XXV.  Filariasis,    413 

Occurrence,    4*3 

Parasitology,   413 

The  Filaria  Nocturna,   414 

Technic  of  Examination,   418 

Staining  the  Filariae,   419 

Hemoglobin  and  Erythrocytes,   4J9 

Leucocytes,    42° 

Diagnosis,    421 

XXVI.  Fractures,   '   42r 

XXVII.  Gastritis,    421 

Acute  and  Chronic  Forms,    42r 

Hyperchlorhydria,  Hypochlorhydria,  Gastric  Achylia,  Gastric 

Dilatation,  Gastric  Neurasthenia,   422 

Diagnosis,    423 

XXVIII.  Gastric  Ulcer,   423 

Hemoglobin  and  Erythrocytes,    423 


xx"  TABLE  OF  CONTENTS. 

Effect  of  Hemorrhage  and  Emesis,   ^ 

Leucocytes,    ...    4  * 

Diagnosis,    ....  424 
6       '    425 

XXIX.   (  1  LAN  DKKS,  

  425 

XXX.  Gonorrhea,    . . 

  426 

XXXI.  Gout,  

Alkalinity,  Fibrin,  and  Uric  Acid' '. " "  If  a 

Cellular  Elements,   A™ 

Perinuclear  Basophilia,                     42  7 

XXXII.  Hemorrhagic  Diseases, 

Specific  Gravity,   42 1 

Bacteriology,   ...    42  7 

Alkalinity ,  :V  "///////.'.'.'.'.[ 4*l 

Coagulation,   4£ 

Hemoglobin  and  Erythrocytes,    42 

Leucocytes,    ....  ' 

Blood  Plaques,   429 

n     '    430 

XXXIII.  Hepatic  Cirrhosis,  

Anemia  in  Atrophic  Cirrhosis,  43° 

Effect  of  Ascites,   43 

Anemia  in  Hypertrophic  Cirrhosis",              43  J 

Leucocytes  in  Atrophic  and  Hypertrophic  Cirrhose's' "  £2 

Diagnosis,   T*5  ■ 

XXXIV.  Hydatid  Disease, 

  433 

XXXV.  Herpes  Zoster,  . . 

'    434 

XXXVI.  Icterus,    ; 

Fibrin,  Coagulation,  Specific  Gravity,' and  Alkalinity," Ill 

Hemoglobin  and  Erythrocytes,    . . .'   7^7 

Leucocytes,  ,     4^ 

Diagnosis,      4^ 

XXXVII.  Influenza,  . .  ' ' ' 
  430 

XXXVIII.  Insolation, 

  437 

XXXIX.  Intestinal  Helminthiasis,   g 

Parasites  Causing  Anemia,  43o 

Factors  of  the  Blood  Changes,             •' 43 

Hemoglobin  and  Erythrocytes,      439 

Bothriocephalus  Anemia,   439 

Ankylostomiasis  Anemia,  'm'm\ "  * " "  39 

Leucocytes,      440 

J     '    440 

XL.  Intestinal  Obstruction, 

  441 

XLI.  Kala-azar,  

Parasitology,      441 

Leishman-Donovan  Bodies,  441 

Hemoglobin  and  Erythrocytes,                      til 

Leucocytes,     443 

Diagnosis,      443 

XLII.  Leprosy,   

  444 

XLIII.  Malarial  Fever, 

Parasitology,   * 44  ^ 

Developmental  Cycle  of  the  Malarial"  Parasite  in  Man, 44  c 
Developmental  Cycle  of  the  Malarial  Parasite  in  the  Mosquito'  aa6 

Varieties  of  the  Malarial  Parasite, .. .  '  77„ 

  44/ 


TABLE  OF  CONTENTS.  XX111 

Page 

The  Parasite  of  Tertian  Fever,   448 

Infections  with  Single  and  Multiple  Groups,    448 

Anticipation  of  the  Paroxysm,    449 

Intracellular  Hyaline  Forms,    449 

Intracellular  Pigmented  Forms,   45° 

Segmenting  Forms,   45 1 

Extracellular  Pigmented  Forms,    45  2 

Flagellate  Forms,   453 

Degenerate  Forms,    454 

The  Parasite  of  Quartan  Fever,    454 

Infections  with  Single  and  Multiple  Groups,    454 

Intracellular  Hyaline  Forms,    454 

Intracellular  Pigmented  Forms,   455 

Segmenting  Forms,    45 6 

Extracellular  Pigmented  Forms,    456 

Flagellate  Forms,  -   45  7 

Degenerate  Forms,    45  7 

The  Parasite  of  Estivo-autumnal  Fever,    457 

Irregularities  in  Time  of  Developmental  Cycle,   45  7 

Disc-  and  Ring-shaped  Forms,   45 8 

Pigmented  Forms,    45 8 

Segmenting  Forms,    459 

Erythropyknosis,    459 

Spherical,  Ovoid,  and  Crescentic  Forms,    460 

Flagellate  Forms,   461 

Degenerate  Forms,    461 

Pigmented  Leucocytes  and  Phagocytosis,   462 

Differential  Table  of  the  Malarial  Parasites,    463 

Technic  of  Examination,   464 

Artefacts  in  Fresh  Blood  Specimens,   465 

Hemoglobin  and  Erythrocytes,    466 

Causes  of  Malarial  Anemia,   466 

Anemia  in  the  Regularly  Intermittent  Fevers,    466 

Anemia  in  Estivo-autumnal  Fever,    467 

Anemia  in  Malarial  Cachexia,    468 

Nucleated  and  Deformed  Erythrocytes,    468 

Types  of  Post-malarial  Anemia,   469 

Leucocytes,    469 

Differential  Changes,    47° 

Blood  Plaques,   47 1 

Diagnosis,    471 

XLTV.  Malignant  Disease,    472 

Carcinoma,    47 2 

Fibrin,  Coagulation,  Specific  Gravity,  and  Alkalinity,  472 

Glycemia,    47 2 

Parasitology,   473 

Hemoglobin  and  Erythrocytes,  -   473 

Regeneration  of  the  Blood  after  Operation,    474 

The  Oligocythemia  and  Polycythemia  of  Gastric  Cancer, . .  474 

Deformed  and  Nucleated  Cells,   475 

Leucocytes,   475 

Frequency  of  Cancer  Leucocytosis,    475 

Causes  of  Cancer  Leucocytosis,   476 

Range  of  the  Leucocytes  in  Different  Forms  of  Cancer,   . .  476 

Digestion  Leucocytosis  in  Gastric  Cancer,   477 

Differential  Changes,    477 

Sarcoma,    478 

General  Features  of  the  Blood,  -  -  -  478 

Cytology,  -  -  -  478 


XXIV 


TABLE  OF  CONTENTS. 


I'm: 

  47 

Diagnosis,    ^79 


Hemoglobin  and  Erythrocytes,   

Leucocytes. 


479 

Bacteriology,   '  ffi 


\LV.   M  VI.ICNANT  IOndocarditis 


Hemoglobin  and  Erythrocyte^           '  ^ 

Leucocytes,   4g 

Diagnosis,      4R3 

XLVI.  Malta  Fever,  V 

'    484 

XL VII.  Measles,.... 

'    485 

XLVIII.  Meningitis,  a, 

  400 

XLIX.  Myxedema,   4gg 

L.  Nephritis,   

Factors  of  the  Blood  Changes',                 ' 

The  Edema  of  Anemia,  ..,   4g; 

Specific  Gravity,  Fibrin,  Coagulation," and  Alkalinity," l0o 

Bacteriology,    J   ^y 


Hemoglobin  and  Erythrocytes,                   

Anemia  in  Acute  and  Chronic  Parenchymatous  Nephritis' 400 

Polycythemia,   r  ^y 

Anemia  in  Chronic  Interstitial  Nephritis,"        tol 

Leucocytes,      4y 

Uremia,     

Diagnosis,  .   

5    492 

LI.  Nervous  and  Mental  Diseases,  ,Q2 

BrainTumot136"'  NeUralgia'  Akatama>  a^d  Er'yth'ro  melalgia',  492 
Neurasthenia,  Hypochondriasis,  and' Hysteria, IqI 

General  Paresis,  Dementia,  Melancholia,  and  Mania,  Ill 

Convulsions,  Apoplectiform  Attacks,  and  Acute  Delirium,  1q< 

Epilepsy,  Chorea,  and  Tetany,  ,   ^7 


LIE  Obesity,   

  498 

LIII.  Osteomalacia,  ...  0 
  498 

LIV.  Pancreatitis,  . . 

  499 

LV.  Pericardial  Effusion, 

LVI.  Peritonitis, 

  5°° 

LVII.  Pertussis,  . . 

  502 

LVIII.  Pleurisy,   

Serous  Pleurisy,  ,    

Purulent  Pleurisy,  

Diagnosis,     ~q4 

LIX.  Pneumonia, 

General  Features  of  the  Blood," .........][.[ 5°5 

Bacteriology,       5  5 

Hemoglobin  and  Erythrocytes,    .  .  .  .  .  .  .  .  .  .  .  5°5 

Leucocytes,     ' 

Relation  of  Leucocytosis  to  Intensity  of"  Infection, ?q7 

frequency  and  Extent  of  Leucocytosis,  

Effect  of  Induced  Leucocytosis,   "coo 

Effect  of  Antipyresis,  

Differential  Changes,....  \° 


TABLE  OF  CONTENTS.  XXV 

Page 

Blood  Plaques,   5*° 

Diagnosis,   511 

LX.  Poisoning,   -   511 

LXI.  Rabies,    5*3 

LXII.  Relapsing  Fever,    5J4 

Parasitology,    5r4 

Lowenthal's  Reaction,    5 16 

Hemoglobin  and  Erythrocytes,    5 16 

Leucocytes,   5*6 

Diagnosis,   5*7 

LXIII.  Rheumatic  Fever,    5 18 

Coagulation,  Fibrin,  and  Alkalinity,   5 18 

Bacteriology,    5 18 

Hemoglobin  and  Erythrocytes,    5I9 

Leucocytes,   5 20 

Diagnosis,   52° 

LXIV.  Scarlet  Fever,    521 

Coagulation,  Fibrin,  and  Specific  Gravity,    521 

Bacteriology,    521 

Hemoglobin  and  Erythrocytes,    522 

Leucocytes,   523 

Blood  Plaques,   524 

Diagnosis,   525 

LXV.  Septicemia  and  Pyemia,   525 

General  Features  of  the  Blood,   S25 

Serum  Reaction,    525 

Bacteriology,   -  52^ 

Hemoglobin  and  Erythrocytes,    527 

Deformed  and  Nucleated  Erythrocytes,    5  28 

Leucocytes,   529 

Differential  Changes,    529 

Diagnosis,   53° 

LXVI.  Spotted  Fever  of  Montana,    531 

LXVII.  Syphilis,   532 

Bacteriology,    532 

Hemoglobin  and  Erythrocytes,    532 

Syphilitic  Chlorosis  and  Pernicious  Anemia,    532 

Effect  of  Mercury  and  Iodides  on  the  Blood,   533 

Justus'  Test,   533 

Leucocytes,   534 

Diagnosis,   535 

Blood  Plaques,   535 

LXVIII.  Tetanus,   535 

LXIX.  Tonsillitis,    535 

LXX.  Trichuriasis,   536 

LXXI.  Trypanosomiasis,   538 

Parasitology,      538 

Cellular  Elements,   541 

Diagnosis,   541 

LXXII.  Tuberculosis,   54* 

General  Features  of  the  Blood,   54 1 

Bacteriology,    542 

Serum  Reaction,    54 2 


xxvi 


TABLE   OF  CONTENTS. 


Hemoglobin  and  Erythrocytes,   

Anemia  in  Pulmonary  Tuberculosis,   IZZ 

Anemia  in  Bone  Tuberculosis,   

Anemia  in  Tuberculous  Adenitis,  Meningitis^ 'pericarditis " 
Pleurisy,  and  Peritonitis,  and  in  Genitourinary  Tubercu- 
losis,   •■ 

Leucocytes,    

Differential  Changes, 

Range  of  the  Leucocytes  in  Pulmonary  Tuberculosis " Ill' 
Range  of  the  Leucocytes  in  Bone  Tuberculosis,  '  IZg 

Range  of  the  Leucocytes  in  Acute  Miliary  Tuberculosis,  Tuber- 
culous Adenitis,  Pleurisy,  Peritonitis,  Pericarditis,  and  Men- 
ingitis, and  in  Genito-urinary  Tuberculosis,  .  Kd0 
Effect  of  Secondary  Septic  Infections, . . 

Diagnosis,     b^J 

6        '    550 

LXXIIL  Typhus  Fever,  

Parasitology,      |5° 

Hemoglobin  and  Erythrocytes,  "  ] " "  55° 

Leucocytes,   .'     55 

Diagnosis.  ....    ^I 

&        '    551 

LXXIV.  Vaccination,  . .  •_ 

'    552 

LXXV.  Valvular  Heart  Disease,    q 

Stage  of  Compensation,   ^  . 

Acute  Rupture  of  Compensation,  '. 5A0 

Effect  of  Stasis,   552 

LXXVI.  Varicella,  

LXXVII.  Variola,   [  [ 554 

Parasitology,   I f f 

Hemoglobin  and  Erythrocytes,                       "  I A 

Leucocytes,    

Blood  Plaques,  .".".*."." [....]][[[[[[  ] ^° 

Diagnosis,   ^7 

LXXVIII.  Yellow  Fever,    g 

Fibrin  and  Coagulation,   Jrg 

Bacteriology,  .*    

Hemoglobin  and  Erythrocytes,               clQ 

Degenerative  Changes, . . .  

^ucocytes>  •  "."";;;!:"!;.■.;.":  <60 

Diagnosis,   ^6o 


List  or  Illustrations,  ;   xxvii 

Index  oe  Authors  ...  ^ 

  561 

Index  oe  Subjects,  


LIST  OF  ILLUSTRATIONS. 


.  ....Frontispiece. 
The  Leucocytes,   r 

Page 

Plate 

I.  The  Erythrocytes,   

20£ 

II.  The  Leucocytes,   3 

.  228 

III.  Leucocytosis,   

IV.  Myelogenous  Leukemia,  ; 3°6 

V.  Lymphatic  Leukemia,   317 

VI.  The  Tertian  Malarial  Parasite,   449 

VII.  The  Quartan  Malarial  Parasite,  -   455 

VIII.  The  Estivo-autumnal  Malarial  Parasite,   459 

CHART      •  •       A       •  --279 
I.  Pernicious  Anemia,   /y 

II.  Myelogenous  Leukemia,   31 

III.  Multiple  Infections  in  Malarial  Fever,   447 

Figure  ?a 

1 .  Blood  Lancet,  -  -  -  -  

2.  Proper  Distribution  of  Cells  in  a  Blood  Film,  ------------ 3" 

3 .  Zones  of  Rouleaux  and  of  Isolated  Cells  in  a  Fresh  Blood  Film,   30 

4.  Dare's  Hemoglobinometer,    4° 

5.  Horizontal  Section  of  Dare's  Hemoglobinometer,   4* 

6.  Method  of  Filling  Blood  Chamber,   43 

7.  Von  FleischPs  Hemometer,   43 

0   Tinted  Wedge  of  von  Fleischl's  Hemometer,   43 


9   Capillary  Pipette  of  von  Fleischl's  Hemometer,   43 

10.  Method  of  Using  von  Fleischl's  Hemometer,   40 

11   Light-proof  Box  for  von  Fleischl's  Hemometer,   4° 

12.  Method  of  Using  Oliver's  Hemoglobinometer,    5* 

13.  Gowers' Hemoglobinometer,   5 

14.  Thoma-Zeiss  Hemocytometer,  -   57 


15.  Thoma-Zeiss  Counting 


Chamber,  '■  .--    5 8 


16 


Ruled  Area  of  Thoma-Zeiss  Counting  Chamber,   59 


60 


17.  Ruled  Area  of  Zappert's  Counting  Chamber, 

18.  Method  of  Filling  the  Hemocytometer,   j£ 

19.  Plan  of  Counting  the  Erythrocytes,   3 

20.  Ocular  Diaphragm,   5 

21.  Expelling  Contents  of  the  Erythrocytometer,  -  •  -  -  -  «/ 

22.  Cross-section  of  Durham's  Blood  Pipette,   06 

23.  Method  of  Using  Oliver's  Hemocytometer,   7 

24.  Superimposing  the  Charged  Cover-glass,   77 

25.  Drawing  Apart  the  Cover-glasses,   77 

26.  The  Cover-glasses  after  Separation,   7 

27.  Spreading  a  Film  with  Two  Glass  Slides,   7 

28.  Spreading  a  Film  with  Cigarette  Paper,   7 

29.  Oven  for  Fixing  Blood  Films,   79 

xxvii 


XXV11J 


I  1ST  or  ILLUSTRATIONS. 


Figure 

30.  Daland's  Hematokrit, .  Paos 

31.  Engel's  Alkalimetcr   ^ 

32.  Dare's Hemo-alkalimeter,  i)7 

33-  Milian's  Coagulation  Test,. .  99 

34-  Wright's  Coagulometcr,   100 

35.  Fontaine's  Cryoscope,  \ 101 

36.  Sorby-Beck  Microspectroscope  105 

37-  Sorby  Tubular  Cell,   J°7 

38-  Aspirating  Tube  for  Blood  Culturing] 108 

39-  Rouleaux  Formation  and  Fibrin  in  Normal  Blood 

40.  Hyperinosis,   '   I3° 

41-  Mechanism  of  Toxin-ceil  Union",  137 
42.  Elaboration  and  Action  of  Antitoxin,  " 152 

43-  Mechanism  of  Hemolysis,   I53 

44-  Mechanism  of  Antihemolysis,  I5£ 

45-  Blood  Spectra,     r56 

46.  Deformities  of  Size  and  Shape  of '  the  ErVthrocyteV 

47-  Degenerative  Changes  in  the  Erythrocytes,.              "  o 

48.  Megaloblasts,  "    ia4 

49-  Atypical  Forms  of  ErythroblasVs," 190 

50.  Granular  Basophilia,      I93 

51.  Changes  in  the  Erythrocytes  in  Chlorosis J?9 

52.  Changes  in  the  Erythrocytes  in  Pernicious  Anemia, III 

53-  Atypical  Myelocytes  in  Myelogenous  Leukemia,  „° 

54-  Atypical  Polynuclear  Neutrophils  in  Myelogenous  Leukemia,' .' \\l 

55-  Atypical  Lymphocytes  m  Lymphatic  Leukemia,  ill 
50.  Positive  Serum  Reaction  in  Enteric  Fever,  3 *£ 
57-  Pseudo-reaction  in  Enteric  Fever             '  "  39? 

58.  Bacillus  Typhi  Abdominalis,  ....  39° 

59.  Filaria  Nocturna  in  Fresh  Blood,   397 

60.  Filaria  Nocturna,  showing  Granular  Degeneration, "  " ""  " " 

61 .  Filaria  Nocturna,  showing  Changes  in  Shape, . .  TZo 
02.  Leishman-Donovan  Bodies,     4 

63.  Spirilla  of  Relapsing  Fever^  WW. 4i2 

64.  Trypanosoma  Gambiense,  .    4 

  540 


INTRODUCTION. 


The  rapid  growth  and  development  of  hematology  during 
recent  years  and  the  practical  application  of  many  of  its  teachings 
to  the  diagnosis  of  various  diseases  have  made  this  science  one 
which  no  progressive  medical  man  can  afford  to  disregard.  Ex- 
amination of  the  blood  gives  definite  clinical  information  which 
may  be  profitable  both  to  the  practitioner  of  internal  medicine 
and  to  the  surgeon,  and  the  procedure  is  capable  of  throwing  light 
upon  the  diagnosis  in  so  wide  a  range  of  pathological  conditions 
that  it  is  difficult  to  single  out  any  disease  in  which  it  may  not 
be  of  some  utility,  either  as  positive  or  as  negative  evidence. 

In  the  light  of  our  present  knowledge  of  the  subject,  clinical 
information  of  two  kinds  may  be  derived  from  hematology, 
namely,  findings  which  are  pathognomonic  of  certain  diseases; 
and  auxiliary  data  which,  if  considered  in  connection  with  other 
clinical  manifestations,  may  prove  either  essential  or  helpful  in 
establishing  the  precise  nature  of  a  disease. 

The  list  of  diseases  in  which  pathognomonic  blood  findings 
are  met  with  includes  leukemia,  the  malarial  fevers,  relapsing 
fever,  filariasis,  trypanosomiasis,  and  piroplasmiasis.  In  per- 
nicious anemia  a  typical  picture  is  also  found,  if  two  conditions 
capable  of  exciting  identical  blood  changes  are  excepted,  the  pro- 
found secondary  anemias  due  to  certain  intestinal  parasites  and  to 
nitrobenzene  poisoning. 

The  blood  examination  affords  data  which,  although  not 
pathognomonic,  are  nevertheless  essential  for  the  diagnosis  of 
chlorosis,  Hodgkin's  disease,  splenic  anemia,  chloroma,  Osier's 
disease,  multiple  periostitis,  kala-azar,  and  secondary  anemias 
dependent  upon  various  causes.  For  example,  in  chlorosis  a 
definite  group  of  blood  changes  must  exist  in  order  to  justify 
an  unconditional  diagnosis,  although  the  occurrence  of  these 
changes,  unassociated  with  other  equally  definite  clinical  signs, 
is  insufficient  evidence  of  this  disease.  In  Hodgkin's  disease, 
a  condition  indistinguishable  from  leukemia  by  an  ordinary 
physical  examination,  the  absence  of  a  leukemic  state  of  the 
blood  at  once  excludes  the  latter  disease.  In  the  secondary 
anemias,  it  is  obvious  that  the  blood  count  alone  can  give  the 

xxix 


XXX 


I  INTRODUCTION. 


exact  clue  to  the  condition,  by  determining  the  degree  and  char 
acter  of  the  blood  impoverishment,  and  by  tracing  from  time  to 
time  its  progress.  In  this  connection  it  is  important  to  remember 
that  pallor  may  go  hand  in  hand  with  a  normal  hemoglobin  pcr 
centage  and  erythrocyte  count,  and  that,  on  the  other  hand,  a  high 
color  by  no  means  invariably  signifies  that  the  individual  is  noi 
anemic.  In  addition  to  the  diseases  just  named,  hematology  gives 
information  which  is  often  of  great  assistance  in,  although  not 
essential  for,  the  diagnosis  of  such  conditions  as  enteric  fever, 
sepsis,  pneumonia,  pertussis,  appendicitis,  diabetes,  rabies,  syph- 
ilis, gastric  ulcer,  malignant  disease,  helminthiasis,  the  exanthe- 
mata, the  hemorrhagic  diseases,  and  suppurative  processes. 
Clinical  experience  has  repeatedly  illustrated  the  value  of  the 
serum  reaction  in  enteric  and  Malta  fevers  and  in  dysentery;  of 
Williamson's  test  in  diabetes  mellitus;  of  eosinophilia  in  trichuri- 
asis, in  echinococcus  disease,  and  in  other  forms  of  helminthiasis ; 
of  mononucleosis  in  variola  and  in  pertussis ;  and  pf  leucocytosis 
and  iodophilia  in  sepsis,  in  suppurative  lesions,  and  in  many  of 
the  acute  infections.  The  forensic  use  of  Bordet's  test  for  the 
identification  of  blood  stains,  and  the  application  of  cryoscopy  to 
the  diagnosis  of  renal  disease  are  also  of  practical  utility. 

Negative  results  from  a  blood  examination  also  possess  diag- 
nostic value  within  certain  limits,  but  too  great  reliance  upon 
evidence  of  this  sort  more  often  proves  delusive  than  helpful.  In 
a  patient  whose  waxy,  yellowish  facies  suggests  with  equal  force 
pernicious  anemia,  chronic  nephritis,  and,  perhaps,  liver  cirrhosis, 
the  absence  of  characteristic  blood  changes  is  sufficient  to  exclude 
the  first-named  condition.  But  failure  to  detect  the  malarial 
parasite  does  not  necessarily  exclude  malarial  fever;  a  negative 
serum  test  does  not  absolutely  rule  out  enteric  fever;  and  an 
absence  of  leucocytosis  cannot  be  regarded  as  an  infallible  sign 
that  a  suppurative  focus  does  not  exist,  nor  does  it  always  indicate 
the  benignity  of  a  neoplasm.  Negative  evidence,  then,  is  usually 
to  be  considered  merely  suggestive,  the  real  pertinence  of  the  hint 
thus  obtained  depending  upon  its  correlation  with  other  physical 
signs  and  symptoms. 

The  significance  of  positive  findings  in  bacteriological  investi- 
gations of  the  blood  is  patent,  and  recent  improvements  in  technic 
have  made  this  means  of  research  simple,  dependable,  and  certain. 
Blood  cultures  furnish  conclusive  information  in  general  septi- 
cemia, pneumonia,  enteric  fever,  Malta  fever,  plague,  scarlet 
fever,  malignant  endocarditis,  and  similar  conditions  in  which 
bacteria  invade  the  blood  stream. 

At  the  present  time  the  most  useful  information  furnished  by 


INTRODUCTION. 


xxxi 


hematology  has  been  derived  from  study  of  the  cellular  elements 
of  the  blood,  but  closer  familiarity  with  the  chemistry  of  this  tissue, 
still  an  undeveloped  science,  will  undoubtedly  in  the  near  future 
afford  not  only  more  tangible  clues  to  the  etiology  and  pathology 
of  the  blood  diseases,  but  also  will  bring  to  light  additional  facts 
which  may  be  applied  to  the  diagnosis  of  these  and  other  maladies. 
The  study  of  the  coagulation  time  of  the  blood  is  of  practical 
utility  in  the  study  of  purpura,  hemophilia,  jaundice,  and  other 
conditions  characterized  by  slow  clotting  and  by  a  tendency 
toward  hemorrhage. 

The  technic  of  blood  examinations,  such  as  described  in  the 
following  pages,  is  neither  elaborate  nor  difficult  to  master.  Nec- 
essarily, it  must  be  rigidly  exact,  but  no  more  so  than  any  other 
branch  of  physical  diagnosis,  if  the  worker  is  content  only  with  the 
best  results.  To  acquire  a  good  working  knowledge  of  hema- 
tology takes  but  a  fraction  of  the  time  and  application  that  one 
must  spend  in  familiarizing  one's  self  with  the  most  common  heart 
murmurs  or  chest  signs,  and  the  time  thus  spent  equips  the  physi- 
cian with  an  additional  diagnostic  agent  of  the  greatest  value.  If 
the  newly  graduated  physician  would  provide  himself  with  a 
microscope  and  a  set  of  blood  instruments,  and  systematically 
study  the  blood  in  the  various  general  diseases  which  he  encounters 
in  practice,  many  a  slip-shod  diagnosis  might  be  avoided,  and  a 
great  stride  forward  made  in  popularizing  this  practical  branch 
of  clinical  diagnosis. 


"L'avenir  appartient  a  V  hematologic  C'est  elle  qui  nous  apportera  la  solu~ 
Hon  des  grands  problemes  nosologiques.  Elle  doit  nous  apparaitre  comme  une 
vaste  science  puisant  ses  materiaux  dans  toutes  les  branches  des  connaissances 
biologiques  et  recueillant  les  diver  ses  notions  de  Vhumorisme  ancien  pour  les 
rajeunir  et  les  completer  a  la  lumiere  des  decouvertes  modernes  en  anatomie,  en 
physiologie,  en  chimie  biologique  et  en  pathologies 

Georges  Hayem. 


SECTION  I. 


EXAMINATION  OF  THE  BLOOD  BY 
CLINICAL  METHODS. 


SECTION  I. 


EXAMINATION  OF  THE  BLOOD  BY  CLINICAL 
METHODS. 


r  A  systematic  examination  of  the  blood  by 

General     clinical  methods  of  established  utility  includes 
bCHEMA.      the  following  different  processes: 

I.    Microscopical  examination  of  the  fresh  blood. 
II.    Estimation  of  the  percentage  of  hemoglobin. 

III.  Counting  the  erythrocytes  and  the  leucocytes. 

IV.  Microscopical  examination  of  the  stained  specimen. 
These  four  procedures,  which  should  invariably  be  included  in 

every  clinical  blood  report,  furnish  the  most  important  informa- 
tion to  be  derived  from  hematological  study,  and  are  sufficient 
for  routine  clinical  work.  In  certain  instances  in  which  more  de- 
tailed investigation  of  special  points  is  sought,  it  may  be  thought 
advisable  to  supplement  the  above  plan  by  employing  one  or 
more  of  these  remaining  procedures : 

V.    Counting  the  blood  plaques. 

VI.    Estimation  of  the  relative  volumes  of  corpuscles  and 
plasma. 

VII.    Estimation  of  the  specific  gravity. 
VIII.    Estimation  of  the  alkalinity. 
IX.    Determination  of  the  rapidity  of  coagulation. 
X.    Cryoscopical  examination. 

XL    Estimation  of  the  resistance  of  the  erythrocytes. 
XII.    Spectroscopical  examination. 

XIII.  Bacteriological  examination. 

XIV.  Determination  of  the  serum  reaction. 
XV.    Medico-legal  tests  for  blood. 

I.    MICROSCOPICAL  EXAMINATION  OF  THE  FRESH 

BLOOD. 

The  finger-tip  or  the  lobe  of  the  ear  is  the  part 
Obtaining  the  usually  selected  from  which  to  obtain  the  blood, 
Specimen.     by  puncture,  for  examination.    The  former  site 
is  preferable  in  most  instances,  owing  to  its  con- 
3  33 


34       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


venient  situation  and  case  of  manipulation;  but  in  nervous  indi- 
viduals and  in  children  the  car-lobe  may  be  chosen,  because  of  its 
limited  sensibility  and  on  account  of  the  patient's  inability  to 
watch  the  operation. 

The  puncture  may  be  made  with  one  of  the  special  blood 
lancets  devised  for  this  purpose,  or,  in  lieu  of  such  an  instrument, 
a  Hagedorn  or  spear-pointed  surgical  needle  or  a  new  sharp- 
pointed  steel  pen  from  which  one  nib  has  been  twisted  off,  will 
answer  the  purpose  equally  as  well.  The  author  is  accustomed 
to  use  a  small  steel  trocar  blade,  mounted  on  a  metal  shaft  which 
screws  into  an  outer  barrel  by  means  of  a  thread.  By  the  use 
of  a  threaded  locking-nut,  any  desired  length  of  the  trocar  may 
be  exposed,  so  that  the  depth  of  the  wound  may  be  controlled 
at  will,  irrespective  of  the  force  used  to  drive  the  point  of  the 
instrument  through  the  skin.  It  is  not  necessary  to  sterilize  the 
puncture-needle:  wiping  it  with  a  towel  wet  with  alcohol  is  all 
that  is  required  in  ordinary  examinations.  Of  course,  should 
the  patient  happen  to  be  syphilitic  or  septic,  it  is  safer  to  pass 
the  blade  through  an  alcohol  flame  after  having  used  it. 

Having  chosen,  say,  the  patient's 
middle  or  ring-finger,  the  part  is  first 
thoroughly  cleansed  with  alcohol  or 
ether  and  then  with  water,  and  wiped 
perfectly  dry  with  a  clean,  lint-free 
towel,  which  may  then  be  folded  into 
a  pad  and  slipped  behind  the  finger  to  isolate  it  from  the 
neighboring  digits,  and  to  serve  as  a  cushion  for  the  back 
of  the  hand.  The  operator,  holding  the  patient's  hand  in  a 
firm,  steady  position,  makes  the  puncture  with  a  rapid  motion 
of  the  wrist,  such  as  one  is  accustomed  to  use  in  percussing 
the  thorax,  the  depth  of  the  wound  being  just  sufficient  to 
cause  a  free  flow  of  blood  in  good-sized  drops,  unaided  by 
the  slightest  pressure  on  the  finger  other  than  that  necessary  to 
start  the  initial  oozing.  The  needle  should  be  aimed  so  as  to 
strike  a  point  in  the  center  of  the  flexor  surface  of  the  finger,  just 
back  of  the  extreme  tip.  The  blood  drop  to  be  used  for  the  ex- 
amination should  under  no  circumstance  be  squeezed  from  the 
finger,  for  blood  secured  in  this  manner  is  certain  to  be  more  or 
less  highly  diluted  with  lymph  from  the  surrounding  tissues — a 
condition  which  will  lead  to  erroneous  results,  especially  to  lower 
hemoglobin,  specific  gravity,  and  corpuscular  estimations  than 
actually  exist.  In  severe  anemias,  especially  in  those  of  the 
pernicious  type,  the  bloodless  condition  of  the  superficial  ves- 
sels is  sometimes  so  marked  that  it  may  be  impossible  to  obtain 


MICROSCOPICAL  EXAMINATION  OF  THE  FRESH  BLOOD.  35 

enough  blood  for  the  examination  by  an  ordinary  puncture,  even 
from  the  ear-lobe,  which,  as  a  rule,  is  highly  vascular.  Relatively 
deep  incisions  are  unavoidable  in  such  instances.  On  the  con- 
trary, in  most  cases  of  leukemia,  unless  the  coexisting  anemia 
is  of  striking  intensity,  the  blood  usually  flows  very  freely,  and 
may  even  spurt  from  the  wound  in  a  fine  jet  several  inches  in 
height. 

Most  writers  on  hematology  utter  an  emphatic  warning  against 
hemophilics,  in  whom  the  slightest  prick  of  a  needle  may  cause 
troublesome  bleeding.  The  writer  has  never  had  the  misfortune 
to  meet  with  this  accident,  but  recognizes  the  wisdom  of  observ- 
ing the  precaution  to  question  every  patient  concerning  an 
abnormal  tendency  toward  hemorrhage. 

The  observer's  attention  should  be  directed  to  the  color  and 
the  density  of  the  blood  drop  as  it  flows  from  the  puncture,  and 
a  note  taken  of  the  various  macroscopical  changes  which  may 
occur,  such  as  the  pale,  hydremic  condition  of  the  blood  found 
in  severe  anemias,  the  deep  blue  color  in  cyanosis,  and  the  milky 
appearance  in  leukemia  and  in  diabetes.  These  and  other  altera- 
tions in  the  naked-eye  appearance  of  the  fresh  blood  have  been 
discussed  in  another  section. 

The  first  few  drops  of  blood  which  follow  the 

Preparing  puncture  are  wiped  away,  and  the  site  of  the  in- 
the  cision  freed  from  every  trace  of  moisture,  after 
Slide.  which  a  perfectly  clean  cover-glass,  held  edge- 
wise between  the  thumb  and  forefinger,  is  lightly 
touched  to  the  summit  of  the  next  drop  as  it  oozes  from  the  punc- 
ture, and  is  then  immediately  placed,  blood  side  downward, 
upon  the  surface  of  a  clean  glass  slide.  If  the  cover-glass  and 
the  slide  are  perfectly  clean  and  dry,  and  if  the  drop  is  of  the 
proper  size,  the  blood  will  at  once  spread  out  in  a  thin  film  con- 
sisting of  a  single  layer  of  corpuscles  (Fig.  2),  surrounded  by  an 
outer  zone  in  which  the  cells  are  heaped  up  in  masses  and  rouleaux ; 
this  thicker  area  of  the  specimen  is  unsuited  for  examination 
(Fig.  3).  Gently  heating  the  slide  over  an  alcohol  flame  just 
before  use  will  insure  a  thin,  even  spread.  If  prolonged  study 
of  the  specimen  is  intended,  it  is  advisable  to  exclude  air  from 
the  film,  by  ringing  the  margins  of  the  cover-glass  with  a  thin 
layer  of  cedar  oil  or  vaselin,  but  ordinarily  this  precaution  is 
unnecessary.  In  order  to  prevent  distortion  of  the  corpuscles, 
pressure  must  be  avoided  while  adjusting  the  cover-glass.  If 
the  blood  does  not  spread  of  itself,  without  the  aid  of  pressure, 
it  is  usually  owing  to  the  presence  of  particles  of  dust  or  grease 
between  the  opposed  surfaces  of  the  slide  and  cover-glass. 


36       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


Absolute  cleanliness  of  the  covers  and  slides  is  an  essential 
detail  to  which  too  great  attention  cannot  be  paid,  for  neglect  of 
this  precaution  is  responsible  for  the  majority  of  failures  to  secure 
good  specimens.    Perhaps  the  most  useful  cleansing  agent  is  the 


O  C 


C  GOO  .  rjr  e 


Fig.  2  —  Proper  Distribution  of  the  Corpuscles  in  a  Fresh  Blood  Film  Prepared  for 
Microscopical  Examination. 

solution  popularly  known  as  "acid  alcohol"  (hydrochloric  acid, 
1  part;  absolute  alcohol,  29  parts;  water,  70  parts),  which  quickly 
and  effectually  removes  all  traces  of  grease  and  dirt  from  the  glasses, 
so  that  their  preliminary  soaking  in  soap-suds  or  in  a  strong 
mineral  acid,  as  some 

recommend,  may  be  dis-  A  © 

pensed  with.  The  slides 
and  covers  may  be  con- 
veniently kept  in  closed 
glass  receptacles  contain- 
ing this  solution,  from 
which  they  are  removed 
as  the  occasion  demands, 
being  then  dried  and 
polished  with  a  bit  of 
clean  linen  or  with  tissue- 
paper.  Ordinary  soft 
" toilet-paper"  is  excellent  for  this  purpose, 
measuring  f  X  if  inches  and  of  "No.  1 


Fig. 


Zones  of  Rouleaux  (A)  and  of  Isolated 
Cells  (B)  in  a  Fresh  Blood  Film. 


Oblong  cover-glasses, 
thickness,  are  more 

easily  handled  without  forceps  than  smaller  square  or  circular  slips, 
and  also  have  a  much  larger  surface  than  the  latter,  which  is  often 
decidedly  advantageous. 


MICROSCOPICAL  EXAMINATION  OF  THE  FRESH  BLOOD.  37 

The  use  of  forceps  is  unnecessary  if  care  is  observed  to  hold 
the  cover-glass  in  the  manner  already  directed,  so  that  only  its 
edges  come  in  contact  with  the  thumb  and  ringer. 

The  specimen,  prepared  in  the  manner  just 
Microscopical  described,  is  examined  under  the  microscope 
Examination,  with  both  low  and  high  powers,  a  or  ^  inch 
dry,  and  a  y1-^  inch  oil-immersion,  objective  being 
the  most  satisfactory  lenses  for  the  purpose.  The  substage  con- 
denser and  diaphragm  should  be  adjusted  so  that  the  field  is  but 
moderately  illuminated,  rather  than  flooded  with  a  glare  of  white 
light.  Microscopical  examination  of  the  fresh  blood  film  furnishes 
information  about  the  following  points: 

Changes  Affecting  the  Erythrocytes. — With  a  little  practice  one 
soon  becomes  able  to  detect,  with  a  tolerable  degree  of  accuracy, 
any  conspicuous  decrease  in  the  number  of  erythrocytes,  by  the 
relatively  small  number  of  cells  in  the  field  in  comparison  with 
their  number  in  a  similar  field  of  normal  blood.  With  less  con- 
fidence it  is  also  possible  to  decide  whether  or  not  the  number 
of  erythrocytes  is  much  in  excess  of  the  normal  standard. 

Deficiency  in  hemoglobin  produces  unmistakable  changes  in 
the  appearance  of  the  cells,  those  in  which  this  change  is  well 
defined  appearing  as  pale,  washed-out  bodies  which  stand  in 
striking  contrast  to  the  darker,  yellowish-green  color  of  the  normal 
erythrocytes. 

Abnormal  viscosity  of  the  erythrocytes,  their  tendency  toward 
rouleaux  formation,  the  presence  of  deformities  of  size  and  of 
shape,  and  the  occurrence  of  structural  degenerative  changes 
may  also  be  distinguished  in  the  fresh,  unstained  blood  film. 
Nucleated  erythrocytes  are  not  demonstrable  in  the  fresh 
specimen. 

Changes  Affecting  the  Leucocytes. — A  glance  is  usually  suffi- 
cient to  determine  whether  or  not  the  number  of  leucocytes  is 
markedly  in  excess  of  normal,  but  too  great  dependence  should  not 
be  placed  on  such  a  method  of  detecting  the  presence  or  absence 
of  a  leucocyte  increase,  since  it  is  at  the  best  approximate,  and 
sometimes  erroneous.  As  will  be  explained  elsewhere,  any 
marked  decrease  in  the  number  of  erythrocytes,  the  leucocytes 
remaining  normal,  may  so  increase  the  ratio  of  the  latter  to  the 
former,  that  the  leucocytes  may  be  apparently  increased. 

Having  tentatively  determined  that  an  increase  in  the  total 
number  of  leucocytes  is  present,  it  is  furthermore  possible  for 
one  familiar  with  the  morphology  of  the  unstained  leucocyte  to 
make  a  fairly  accurate  differential  count  of  these  cells,  and  thus 
to  decide  whether  the  increase  is  due  to  a  pure  leucocytosis 


3« 


KX  AM  I  NATION   OK  TIIK 


BLOOD  BY  CLINICAL  METHODS. 


or  to  sonic  form  of  leukemia.  This  distinction  is  not  at  all  diffi- 
cult in  most  instances,  when  one  recalls  the  characteristics  of 
the  several  forms  of  leucocytes  in  the  fresh  blood,  viz.:  small 
lymphocytes,  large  lymphocytes,  and  transitional  forms,  appear- 
ing as  cells  having  a  single  spherical  or  indented  nucleus,  and  a 
clear,  shining,  non-granular  protoplasm ;  polynuclcar  neutrophiles, 
as  cells  with  polymorphous  or  multiple  nuclei,  and  a  protoplasm 
crowded  with  very  fine,  moderately  refractive  granules;  eosino- 
philes,  as  cells  with  a  single  polymorphous  nucleus  or  multiple 
nuclei,  and  a  protoplasm  containing  coarse,  spherical,  highly  re- 
fractive, fat-like  granules;  and  myelocytes,  as  cells  with  a  single 
spherical  or  ovoid  nucleus,  and  a  protoplasm  crowded  with  very 
fine,  moderately  refractive  granules.  It  is,  of  course,  obviously 
impossible  to  distinguish  basophile  cells  in  the  fresh  blood,  as 
well  as  some  of  the  cells  containing  fine  eosinophile  granules, 
but  the  characteristics  noted  above  are  sufficiently  plain  to  justify 
at  least  a  provisional  diagnosis  of  either  of  the  conditions  in  ques- 
tion, which,  in  every  instance,  should  be  verified  by  a  careful 
examination  of  the  stained  specimen. 

While  most  of  the  degenerative  changes  which  affect  the  leuco- 
cytes are  clearly  demonstrable  only  in  the  stained  specimen,  it  is 
still  possible  to  recognize  some  of  the  grosser  examples  of  such  a 
process  by  a  study  of  the  fresh  film.  Vacuolation  of  both  nucleus 
and  protoplasm,  extrusion  of  portions  of  the  cell  substance,  and 
the  various  stages  of  nuclear  disintegration  and  of  apparent  solu- 
tion of  the  protoplasm  are  the  alterations  most  commonly  ob- 
served. In  certain  specimens  " fractured"  leucocytes  are  seen 
with  more  or  less  frequency,  a  cell  thus  affected  being  drawn  out 
into  a  diffuse,  irregularly  shaped  body  with  indistinct  and  ragged 
margins,  about  which  the  cell  granules,  which  have  escaped  from 
the  protoplasm,  are  scattered  in  the  form  of  a  nebulous  mass. 
The  eosinophile  leucocytes  seem  especially  prone  to  undergo 
this  disintegration.  The  exact  significance  of  this  phenomenon 
is  not  clear,  but  it  probably  represents  a  degenerative  change  in 
which  the  cells  have  become  abnormally  vulnerable,  and  thus 
highly  susceptible  to  mechanical  injury  from  the  pressure  of  the 
cover- glass. 

Ameboid  activity  of  the  leucocytes  and  pigmentation  of  these 
cells  are  among  the  other  changes  to  be  observed  in  a  histolog- 
ical examination  of  the  unstained  blood  film. 

Increase  in  Fibrin,  Blood  Plaques,  and  Hemokonia. — The  den- 
sity of  the  fibrin  network  and  the  rapidity  with  which  it  forms 
may  be  studied  as  coagulation  of  the  blood  film  progresses.  Un- 
less the  blood  plaques  are  very  greatly  increased  in  number, 


ESTIMATION  OF  THE  PERCENTAGE  OF  HEMOGLOBIN.  39 

they  are  not  usually  noticeable  in  the  specifnen  prepared  in  the 
ordinary  manner.  The  presence  of  hemokonia,  or  "blood  dust," 
is  at  once  rendered  conspicuous  by  the  rapid  and  incessant  molec- 
ular motion  with  which  these  bodies  are  endowed. 

Blood  Parasites. — The  hematozoa  of  the  malarial  fevers,  the 
spirilla  of  relapsing  fever,  the  organisms  of  trypanosomiasis, 
and  the  embryonic  forms  of  the  parasite  of  filarial  disease  should 
be  studied  in  the  fresh  blood  whenever  this  is  possible,  rather 
than  in  the  fixed  and  stained  film,  since  in  the  latter  the  charac- 
teristic morphology  of  these  parasites  is  greatly  altered  and  their 
motility  lost.  The  stained  specimen  is  more  useful  in  studying 
the  finer  structure  of  these  organisms  than  for  diagnostic  examina- 
tions. 

The  distoma  of  bilharzia  disease,  although,  strictly  speaking, 
a  blood  parasite,  is  not  found  in  the  general  circulation,  since  this 
worm  resides  solely  in  the  portal  vein  and  branches,  the  vena  cava, 
and  certain  veins  of  the  lower  pelvis.  Leishman-Donovan 
bodies  are  obtained  by  puncture  of  the  spleen,  but  they  do  not 
enter  the  peripheral  blood. 

Foreign  bodies,  such  as  free  fat  droplets,  collections  of  extra- 
cellular pigment,  and,  very  rarely,  the  crystalline  bodies  of  Char- 
cot may  also  be  observed  in  the  fresh  specimen  during  the  course 
of  certain  diseases. 

Microscopical  examination  of  the  fresh  specimen  should  form 
the  initial  step  taken  in  every  systematic  examination  of  the 
blood,  since  it  may  be  the  means  of  determining  whether  or  not 
a  more  elaborate  investigation  is  necessary.  By  this  simple  pro- 
cedure an  immediate  diagnosis  may  be  made  in  a  number  of  in- 
stances, while  in  others  the  findings,  although  not  pathogno- 
monic, are  of  distinct  clinical  value.  Close  familiarity  with  the 
normal  histology  of  the  blood  is,  of  course,  essential  for  the  ap- 
preciation of  the  various  pathological  changes  which  have  been 
outlined  above.  Fuller  reference  to  these  changes  has  been 
made  in  other  parts  of  this  book.    (See  Sections  III  and  IV.) 

II.  ESTIMATION  OF  THE  PERCENTAGE  OF  HEMO- 
GLOBIN. 

No  fewer  than  half  a  dozen  different  hemoglo- 
Methods.     binometers,  or  instruments  for  estimating  the 
amount  of  hemoglobin  in  the  blood,  are  in  vogue 
at  the  present  time,  of  which  the  most  reliable  for  general  clinical 
use  are  those  devised  by  Dare,  by  von  Fleischl,  by  Oliver,  and  by 
Gowers.    The  hemometer  of  von  Fleischl  has  been  the  general 


40       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

favorite  for  a  number  of  years,  both  in  this  country  and  on  the 
Continent,  but  in  America,  at  least,  Dare's  hemoglobinometer 
is  rapidly  supplanting  it;  in  England  it  has  been  supplanted  to 
some  extent,  first  by  Gowers'  hemoglobinometer,  and  in  recent 
years  by  the  hemoglobinometer  lately  invented  by  Oliver.  The 
instruments  of  von  Fleischl,  Gowers,  and  Oliver  are  based  upon 
a  similar  principle,  that  of  measuring  the  depth  of  color  of  the 
diluted  blood  by  a  standard  color  scale  of  varying  intensity,  the 
gradations  of  which  correspond  to  different  hemoglobin  values; 
that  of  Dare  uses  undiluted  blood. 

With  this  instrument  a  thin  film  of  undiluted 
Dare's       blood  is  brought  into  direct  comparison  with  a 
Hemoglobin-  standard   semicircular  wedge   of   tinted  glass 
ometer.      ranging  in  color  from  a  claret  red  at  the  thickest 
part  to  a  pale  pink  at  the  thinnest.    The  in- 
strument consists  of  the  following  parts:    (i)  A  capillary  blood 

chamber,  constructed  of 
two  rectangular  plates  of 
polished  glass,  the  op- 
posed surfaces  of  which 
are  so  ground  that,  when 
clamped  together  in  a 
metal  bracket,  a  shallow 
compartment  holding  a 
thin  film  of  blood  is 
formed.  One  plate  is 
made  of  transparent,  the 
other  of  opaque,  glass, 
the  latter  being  next  to 
the  source  of  light,  in 
order  to  soften  its  glare, 
when  the  instrument  is  in 
use.  The  metal  bracket 
of  the  blood  chamber  is 
adjusted  to  the  stage  of 
the  instrument  in  such  a 
manner  that  the  blood 
film  fits  over  an  aperture 
communicating  with  a 
camera  tube  screwed  to 
the  opposite  side  of  the  rubber  case.  (2)  A  graduated  color  standard 
made  of  a  semicircle  of  glass  tinted  with  Cassius'  "golden  pur- 
ple," and  thinning  out  like  a  wedge  with  various  depths  of  color 
corresponding  to  the  tints  of  fresh  blood  containing  different 


z 


Fig.  4. — Dare's  Hemoglobinometer. 

R,  Milled  wheel  acting  by  a  friction  bearing  on  the 
rim  of  the  color  disc;  S,  case  inclosing  color  disc,  and 
provided  with  a  stage  to  which  the  blood  chamber  is 
fitted;  T,  movable  wing  which  is  swung  outward  during 
the  observation,  to  serve  as  a  screen  for  the  observer's 
eyes,  and  which  acts  as  a  cover  to  inclose  the  color  disc 
when  the  instrument  is  not  in  use;  U,  telescoping  camera 
tube,  in  position  for  examination;  V,  aperture  admitting 
light  for  illumination  of  the  color  disc;  X,  capillary 
blood  chamber  adjusted  to  stage  of  instrument,  the  slip 
of  opaque  glass,  W,  being  nearest  to  the  source  of  light; 
Y,  detachable  candle-holder;  Z,  rectangular  slot  through 
which  the  hemoglobin  scale  indicated  on  the  rim  of  the 
color  disc  is  read. 


ESTIMATION  OF  THE  PERCENTAGE  OF  HEMOGLOBIN. 


4' 


percentages 


of  hemoglobin.    It  is  mounted  upon  a  disc  adjusted 


in  the  frame  of  the  instrument,  so  that  it  may  be  revolved  to 
bring  various  portions  of  its  surface  over  an  aperture  directly 
alongside  of  the  one  through  which  the  blood  film  is  visible. 
A  scale,  read  from  the  outside  of  the  instrument,  indicates  in 
units  the  hemoglobin  percentages  from  10  to  120.^  (3)  A  hard 
rubber  case  incloses  the  color  standard  when  the  instrument  is 
in  use,  the  disc  upon  which  the  standard  is  mounted  being  re- 
volved by  turning  a  small  milled  wheel  acting  upon  the  rim  of 
the  disc  by  a  friction  bearing.  To  one  side  of  the  case  a  telescopic 
camera  tube,  fitted  with  an  eye-piece,  is  attached,  while  on  the 
opposite  side  a  stage  furnishes  support  for  the  blood  chamber, 
back  of  which  a  candle,  held  between  a  pair  of  spring  clips,  is 
adjusted.  Two  apertures  of  equal  di- 
ameter, placed  side  by  side  on  the  same 
level,  transmit  the  light  of  the  candle 
through  the  blood  film  and  the  color 
standard  to  the  field  of  vision  inclosed 
by  the  camera  tube.  By  reference  to 
the  accompanying  diagram  (Fig.  5)  it 
will  be  seen  that  the  light  of  the  can- 
dle, J,  equally  illuminates  the  blood 
film  inclosed  between  the  two  rect- 
angular glass  plates,  O  and  P,  and  the 
edge  of  the  color  standard,  L,  mounted 
upon  the  glass  disc,  K.  The  differences 
in  the  two  colors  are  visible  through 
the  two  apertures,  M  and  M7,  commu- 
nicating with  the  camera  tube,  N. 
By  revolving  the  disc  the  tint  of  the 

color  standard  may  be  altered  until  it  matches  that  of  the  blood 
film. 

Method  of  Use. — The  instrument  is  prepared  for  use  by  first 
swinging  outward  the  movable  screen  which  serves  as  a  cover  for 
the  case.  The  two  apertures  overlying  the  blood  film  and  the 
color  scale  are  thus  brought  into  view,  the  direct  light  from  the 
candle  being  shaded  from  the  observer's  eyes  by  the  intervening 
screen.  The  camera  tube  and  the  candle-holder  are  then  fitted 
to  their  attachments  on  opposite  sides  of  the  instrument,  and  a 
candle  adjusted  so  that  the  surface  of  its  "wick  end"  is  just  on 
a  level  with  the  top  of  the  spring  clips. 

The  blood  chamber  is  filled  by  touching  its  edge  to  the  side  of 
a  rather  large  drop  of  blood  as  the  latter  flows  from  the  punc- 
ture, so  that  the  blood  at  once  flows  into  and  fills,  by  capillary 
force,  the  shallow  compartment  between  the  pair  of  glass  plates. 


Fig.    5. —Horizontal  Section 
Dare's  Hemoglobinometer. 


42       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


As  soon  as  this  occurs,  any  excess  of  fluid  which  may  have  adhered 
to  the  outer  surface  of  the  blood  chamber  is  carefully  wiped 
away,  and  the  latter  is  slipped  into  the  tongue,  which  holds  it 
in  position  on  the  stage  of  the  instrument. 

The  candle  having  been  lighted,  the  observer  holds  the  instru- 
ment as  a  field  glass,  and  compares  with  one  eye  the  colors  of 
the  blood  film  and  the  standard  disc  which  are  seen  side  by  side 
in  the  field  of  vision  limited  by  the  camera  tube.  The  disc  is 
made  to  revolve  by  making  short,  quick  turns  with  the  milled 
wheel  until  the  two  colors  are  identical,  and  the  hemoglobin  per- 
centage indicated  by  the  scale  is  then  noted. 

The  color  comparisons  need  not  be  made  in  a  darkened  room, 
although  the  observer  should  avoid  facing  the  direct  sunlight, 
and,  in  order  to  exclude  reflected  light,  should  hold  the  instru- 
ment against  a  dark  surface,  such  as  a  black  coat-sleeve.  When 


various  parts  of  the  instrument,  when  detached,  fit  into  a  small 
leather  carrying- case. 

The  chief  advantage  of  Dare's  instrument,  lies  in  the  fact  that 
dilution  of  the  blood  is  not  required,  and  therefore  errors  due  to 
incorrect  measuring  and  dilution  of  the  blood,  which  must  be  care- 
fully guarded  against  in  the  older  hemoglobinometers,  are  entirely 
eliminated.  A  film  of  whole  blood  also  gives  a  relatively  deep 
and  definite  color,  which  may  be  judged  with  greater  ease  and 
accuracy  than  the  paler  and  more  indefinite  tint  of  a  blood  solu- 
tion. It  is  also  obvious  that  errors  due  to  the  turbidity  of  an 
aqueous  solution  of  leukemic  blood  are  avoidable  by  the  use  of 
an  undiluted  film.  Coagulation  of  the  film  does  not  occur  with 
sufficient  rapidity  to  constitute  a  source  of  error,  since  the  test 
may  be  completed  within  a  few  seconds  after  the  blood  has  been 
drawn. 

Three  years'  constant  use  of  this  hemoglobinometer  in  the 


Fig.  6. — Manner  of  Filling  Blood  Chamber. 


the  observation  is 
completed,  the  two 
glass  plates  of  the 
blood  chamber  are 
removed  from  the 
bracket  by  loosening 
the  screw  which  holds 
them  in  position. 
They  are  then  cleaned 
with  water  and  with 
acid  alcohol,  dried, 
polished,  and  replaced 
in  the  bracket.  The 


ESTIMATION  OF  THE  PERCENTAGE  OF  HEMOGLOBIN.  43 


Jefferson  Medical  Clinic  has  proved  it  the  most  accurate,  sim- 
ple, and  convenient  instrument  for  clinical  purposes.  Its  read- 
ings closely  correspond  to  those  of  Oliver's  hcmoglobinometer, 
and  average  somewhat  higher  than  those  of  the  vonfjFleischl 
instrument.  The  color  standard  of  Dare's  apparatus^  being 
wedge-shaped  and  therefore  gradually  blending  the  tints,  is  open 
to  the  same  criticisms  which  have 
been  urged  against  the  scale  of 
the  hemometer. 

With  this  in- 
Von         strument  the 
Fleischl's    color  of  a  fixed 
Hemometer.  volume  of  blood 
in  an  aqueous 
solution  of  a  definite  strength  is 
compared  with  the  color  of  a 
movable  glass  wedge,  tinted  with 
Cassius'  "golden  purple."  The 
hemometer  consists  of  the  follow- 
ing parts: 

(1)  A  tinted  glass  wedge,  the 
thickest  portion  of  which  is  of  a 

deep  pink  color,  and  the  thinnest  portion  almost  colorless,  with 
every  intermediate  color  gradation  between  the  two  extremes. 
It  is  mounted  in  a  metal  frame  provided  with  a  scale,  graduated 
at  every  five  degrees  from  o  to  120,  the  former  corresponding  to 
the  thinnest,  and  the  latter  to  the  thickest,  part  of  the  wedge. 
The  metal  frame  is  grooved  so  that  it  fits  beneath  (2)  a  small 


Von  Fleischl's  Hemometer. 


I  ?|T|T,T|T|5|°,T,r,T|T|r|uO|T| 

Fig.  8.— Tinted  Glass  Wedge  of  the  von  Fleischl 
Hemometer. 


Fig.  9. — Capillary  Pipette  of 
von  Fleischl's  Hemometer. 


stage,  in  which  it  may  be  moved  backward  and  forward  by  turn- 
ing a  milled  wheel.  In  the  center  of  this  stage  there  is  a  circu- 
lar opening  through  which  the  light  of  a  candle  is  reflected  by  a 
disc  of  calcium  sulphate,  mounted  on  the  pillar  supporting  the 
stage,  like  the  mirror  of  a  microscope.  Back  of  this  opening  there 
is  a  small  oval  slot  through  which  the  scale  of  the  underlying 


44       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

tinted  wedge  is  visible,  when  the  latter  is  adjusted  to  the  stage. 
(3)  A  mixing  chamber,  consisting  of  a  short  metal  tube  closed 
at  the  bottom  by  a  disc  of  glass  and  divided  into  two  equal  com- 
partments by  a  vertical  partition,  fits  accurately  over  the  circular 
opening  in  the  stage.  When  properly  adjusted  to  the  latter,  the 
vertical  partition  exactly  coincides  with  the  upper  edge  of  the 
underlying  tinted  wedge,  so  that  the  upper  compartment  of  the 
chamber  is  illuminated  by  the  dull  white  light  from  the  reflector, 
while  the  lower  compartment  receives  the  color  of  the  tinted 
wedge.  (4)  A  capillary  pipette  mounted  in  a  short  metal  handle, 
used  for  making  the  blood  dilution.  A  single  pipetteful  of  normal 
blood  mixed  with  sufficient  distilled  water  to  fill  exactly  one  of 
the  compartments  of  the  mixing  chamber  gives  a  solution  which 
matches  the  color  of  the  tinted  wedge  opposite  the  mark  100. 
(5)  A  small,  fine-pointed  glass  dropper,  used  for  filling  the  com- 
partments with  water. 

Method  of  Use. — As  a  preliminary  step,  each  compartment  of 
the  mixing  chamber  is  filled  about  one-quarter  full  of  distilled 
water  by  means  of  the  glass  dropper,  to  one  end  of  which  a  rubber 
cap  has  been  fitted.  A  puncture  having  been  made,  as  previously 
directed,  a  measured  volume  of  blood  is  collected  by  bringing  one 
end  of  the  capillary  pipette  lightly  in  contact  with  the  blood  drop 
as  it  oozes  from  the  wound,  so  that  the  tube  is  instantly  filled 
with  blood,  by  capillary  force.  No  difficulty  will  be  experienced 
in  quickly  filling  the  tube  if  it  is  applied  horizontally  to  the  side 
of  the  blood  drop,  rather  than  vertically  to  its  summit,  care  being 
observed  not  to  immerse  the  end  too  deeply.  It  is  needless 
to  add  that  the  interior  of  the  tube  must  be  absolutely  clean 
and  dry,  to  insure  which  a  very  fine  needle  and  thread  may  be 
passed  through  it  just  before  using.  As  soon  as  the  pipette  is 
filled,  every  trace  of  blood  must  be  removed  from  its  outer  surface 
and  the  precaution  taken  to  see  that  the  column  of  blood  is  exactly 
flush  with  the  ends  of  the  tube,  being  neither  bulged  out  nor  de- 
pressed. The  blood  is  then  washed  into  one  of  the  compartments 
of  the  mixing  chamber,  by  forcing  a  stream  of  distilled  water 
through  the  pipette  by  means  of  the  glass  dropper,  this  rinsing 
being  repeated  until  it  is  certain  that  every  trace  of  blood  has  been 
removed.  The  preceding  steps  must  be  carried  out  quickly,  in 
order  to  avoid  errors  arising  from  coagulation  of  the  blood.  The 
blood  and  water  in  the  compartment  are  now  thoroughly  mixed 
by  stirring  with  the  handle  of  the  pipette  until  the  color  of  the 
solution  is  diffused  uniformly,  after  which  water  is  added,  drop 
by  drop,  to  each  compartment  until  they  are  both  filled  exactly 
to  their  brims.    In  doing  this,  no  water  must  be  spilled  on  the 


ESTIMATION  OF  THE  PERCENTAGE  OF  HEMOGLOBIN.  45 

thin  edge  of  the  vertical  partition,  for  should  this  occur,  it  may 
cause  an  overflow  of  the  liquid  from  one  compartment  to  the 
other,  and  thus  alter  the  strength  of  the  blood  solution.  If  the 
latter  should  appear  turbid  or  muddy,  as  it  sometimes  does  with 
leukemic  blood,  a  few  drops  of  a  weak  aqueous  solution  of  potas- 
sium hydrate  may  be  added  to  the  diluent  as  a  preventive  of 
this  change.  The  addition  of  a  little  ether  will  clear  the  solu- 
tion if  the  turbidity  is  due  to  the  presence  of  fat. 

Having  carried  out  the  preceding  steps,  the  mixing  chamber  is 
adjusted  over  the  circular  opening  in  the  stage  of  the  instrument, 
so  that  the  compartment  containing  the  blood  solution  is  upper- 
most, overlying  the  semicircle  illuminated  by  the  clear  white 
light;  while  the  compartment  rilled  with  water  fits  over  the  semi- 
circle, which  receives  the  tint  of  the  underlying  glass  wedge. 
The  remainder  of  the  test,  the  comparison  of  the  color  of  the 
two  compartments,  must  be  completed  by  artificial  light,  prefer- 
ably by  candle-light.  Moderately  bright  illumination  is  better 
than  a  strong  glare,  for  the  latter  interferes  seriously  with  the 
accurate  determination  of  delicate  color  differences.  By  means 
of  the  milled  wheel  the  tinted  glass  wedge  is  moved  backward 
and  forward  until  its  color  precisely  corresponds  to  that  of  the 
diluted  blood.  When  this  occurs,  the  percentage  of  hemoglobin 
"is  read  off  from  the  scale  visible  through  the  oval  slot  in  the  stage 
of  the  instrument. 

While  making  the  color  comparison  the  observer  should  stand 
facing  one  end  of  the  glass  wedge  (not  the  milled  wheel),  so  that 
the  partition  between  the  two  compartments  of  the  mixing  cham- 
ber is  on  a  line  with  the  vertical  axis  of  his  eyes,  the  distance  from 
the  latter  to  the  top  of  the  stage  of  the  instrument  being  about 
ten  or  twelve  inches.  Gross  errors  may  be  avoided  if  the  observa- 
tion is  made  with  one  eye  and  if  the  same  eye  is  habitually  used, 
since  the  two  eyes  may  differ  radically  in  their  sensitiveness  to 
color  impressions.  It  is  important  to  decide  the  color  differences 
as  quickly  as  possible,  for  prolonged  examination  rapidly  dulls 
one's  color  perception,  and  creates  uncertainty  as  to  the  proper 
reading.  It  is  a  good  plan  first  to  bring  into  the  field  of  vision 
the  darkest  portions  of  the  wedge  between  the  figures  100  and 
1 20  of  the  scale,  and  then,  by  short,  sudden  turns  of  the  milled 
wheel,  to  produce  abrupt  color  contrasts  of  from  5  to  10  degrees 
at  each  turn,  until  the  two  tints  approximately  correspond.1 
When  this  point  is  reached,  the  eye  should  be  rested  for  a  few 

1  It  is  important  to  bear  in  mind  the  fact  that  the  judgment  of  color  differences 
is  much  easier  if  marked  contrasts  in  color  value  are  made,  than  if  a  gradual  blend- 
ing of  the  two  tints  is  attempted,  by  slowly  moving  the  wedge  past  the  visual  field. 


46       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


moments,  and  then,  by  a  succession  of  shorter  turns,  the  wedge 
is  again  swept  to  and  fro  until  the  colors  appear  identical.  In 
the  average  instance  an  error  of  about  5  degrees  must  be  antici- 
pated in  spite  of  every  precaution  to  insure  accuracy. 


Fig.  10. — Method  of  Using  the  von  Fleischl  Hemometer. 
Note  that  the  septum  between  the  two  halves  of  the  blood  compartment  is  at  right  angles  to 
the  horizontal  axis  of  the  observer's  eyes.    A  cylinder  of  paper  may  be  fitted  over  the  blood  com- 
partment, to  serve  as  a  camera  tube. 

In  cases  in  which  low  hemoglobin  percentages  (30  per  cent, 
or  less)  are  suspected,  it  is  essential  to  use  two  or  three  pipette- 
fuls  of  blood  in  making  the  dilution,  dividing  the  percentage  indi- 
cated by  the  instrument  by  two  or  three,  as  the  case  may  be. 


♦ 


ESTIMATION  OF  THE  PERCENTAGE  OF  HEMOGLOBIN.  47 

This  precaution  effectually  removes  the  objection  which  has  been 
urged  against  this  instrument  on  account  of  its  inaccuracies  in 
the  determination  of  low  hemoglobin  percentages.  Another 
criticism  of  the  von  Fleischl  instrument  has  been  made  on  the 
ground  that,  since  the  length  of  the  tinted  wedge  visible  through 
the  compartment  of  the  mixing  chamber  includes  a  color  range 
of  20  per  cent.,  it  is  impossible  for  one  to  select  a  single  point  .in 
the  center  of  this  color  for  comparison  with  the  even,  diffuse  tint 
of  the  blood  solution.  This  objection  may  be  overcome  to  a 
great  extent  by  using  a  metal  diaphragm,  provided  with  a  slit 
one-eighth  of  an  inch  in  width,  which  is  placed  over  the  glass 
disc  at  the  bottom  of  the  compartments,  to  limit  the  field  of 
vision.  Adjusted  so  that  the  slit  crosses  at  right  angles  the  par- 
tition separating  the  two  colors,  the  use  of  this  device  cuts  down 
the  field  of  observation  to  a  portion  of  the  glass  wedge  corre- 
sponding to  about  2.5  degrees  on  the  scale. 

The  hemoglobin  percentages  indicated  by  this  instrument 
appear  to  be  low  for  the  blood  of  the  average  healthy  American, 
since  it  is  more  common  to  obtain  readings  of  from  90  to  95  than 
of  the  arbitrary  standard  100,  in  persons  in  whom  there  is  no 
good  reason  to  suspect  subnormal  hemoglobin  values.  In  in- 
struments of  recent  manufacture,  however,  this  fault  is  largely 
corrected. 

In  order  to  exclude  the  light  of  the  candle  from  the  field  of 
vision  while  making  the  color  comparison,  it  is  customary  to 
use  a  tube  of  cardboard  or  stiff  paper,  which  is  slipped  over  the 
mixing  chamber  and  rests  upon  the  platform  of  the  instrument. 
This  sort  of  a  device  answers  very  well  when  the  examination  is 
made  in  a  darkened  room,  as,  for  example,  at  a  patient's  residence. 
In  hospital  work,  however,  the  inconvenience,  sometimes  con- 
siderable, of  being  compelled  to  carry  the  diluted  blood  some 
distance  from  the  bedside  to  a  dark  room  may  be  avoided  by  the 
use  of  a  light-proof  box,  which  may  be  conveniently  carried  from 
ward  to  ward,  so  that  the  test  may  be  completed  at  the  bedside 
(Fig.  11).  A  box  of  this  kind  should  measure  sixteen  inches 
in  height  by  twelve  inches  in  length  and  in  width,  being  fitted 
with  a  hinged  door  which  may  be  fastened  by  a  simple  catch, 
and  provided  with  a  circular  opening  through  which  the  milled 
wheel  of  the  hemometer  projects  when  the  door  is  closed.  A 
metal  camera  tube,  flanged  at  the  upper  extremity  for  the  obser- 
ver's, eye,  pierces  the  top  of  the  box  and  communicates  inside 
with  the  mixing  chamber  of  the  hemometer.  The  tube  fits 
loosely  in  a  circular  opening  in  the  top  of  the  box,  so  that  it  may 
readily  be  raised  and  lowered;   its  diameter  is  a  trifle  greater 


48       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


than  that  of  the  mixing  chamber,  around  which  it  should  fit 
snugly  when  lowered  into  position;  and  its  length  is  governed 
by  a  fixed  collar  outside  the  box,  which  prevents  it  from  slipping 
and  jarring  the  instrument.  Wooden  guides,  such  as  are  used 
for  securing  a  microscope  in  its  box,  are  provided  to  receive  the 


Fig.  ii. — Light-proof  Box  for  the  von  Fleischl  Hemometer. 
The  door  of  the  box  is  closed  and  the  color  comparison  made  through  the  camera  tube. 


Note. — Reichert,  at  the  suggestion  of  Miescher,  has  introduced  a  modification 
of  the  original  von  Fleischl  hemometer,  designed  to  increase  the  accuracy  of  the 
test,  by  making  it  possible,  by  definite  dilution  of  the  blood,  to  select  that  part 
of  the  tinted  wedge  which  is  best  adapted  for  the  examination  of  any  particular 
sample.  This  innovation  was  prompted  by  the  discovery  that  the  intermediate 
portions  of  the  wedge  are  better  adapted  for  obtaining  accurate  readings  than  the 
terminal  parts.  The  principal  modification  of  the  new  hemometer  consists  in 
the  substitution,  for  the  original  capillary  blood  pipette,  of  a  special  mixing  pipette, 
similar  to  a  melangeur,  graduated  so  that  the  blood  may  be  diluted  i  :  200,  1  :  300, 
and  1  :  400  times.  A  table  supplied  with  the  instrument  translates  the  combined 
results  of  the  dilutions  and  the  figures  indicated  by  the  scale  on  the  wedge  into 
absolute  hemoglobin  percentages.  The  instrument  is  also  supplied  with  mixing 
chambers  of  different  depths,  and  with  a  diaphragm  designed  to  limit  the  field  of 
vision.  The  writer  has  had  no  practical  experience  with  the  Miescher-Fleischl  hem- 
ometer, but  an  examination  of  the  instrument  justifies  the  belief  that  its  elaborate- 
ness renders  it  undesirable  for  general  clinical  work.  Its  cost  ($50.00)  is  also  a 
bar  to  many. 

horseshoe  base  of  the  hemometer,  holding  it  firmly  in  such  a 
position  that  when  the  camera  tube  is  lowered  into  place  the 
milled  wheel  of  the  instrument  projects  through  the  opening  in 
the  closed'door.  The  interior  of  the  tube  and  of  the  box  is  painted 
a  dull  black.    A  candle  is  placed  in  position  on  the  floor  of  the 


ESTIMATION  OF  THE  PERCENTAGE  OF  HEMOGLOBIN.  49 

box,  on  a  line  with  the  "mirror"  of  the  instrument.  In  using 
this  device  first  the  candle  within  the  box  is  lighted,  and  the 
hemometer  base  is  slipped  into  place  between  the  wooden  guides. 
The  blood  dilution  having  been  made  in  the  usual  manner, 
the  mixing  chamber  is  then  set  upon  the  platform  of  the  instru- 
ment, and  the  camera  tube,  which  has  been  raised  to  allow  this 
to  be  done,  is  lowered  until  it  telescopes  around  the  mixing  cham- 
ber and  rests  firmly  upon  its  collar.  The  door  of  the  box  is 
now  closed,  and  the  two  compartments  are  brought  into  their 
proper  positions  over  the  glass  wedge  by  turning  the  camera 
tube  from  the  outside  of  the  box,  the  observer  meanwhile  noting 
the  result  by  looking  through  the  flanged  extremity  of  the  tube. 
This  accomplished,  the  projecting  wheel  of  the  instrument  is 
turned  to  and  fro  until  the  colors  of  the  two  compartments  are 
the  same,  when  the  door  is  opened  and  the  percentage  read  off 
from  the  scale  of  the  hemometer.  Care  must  be  observed  to 
see  that  the  exterior  of  the  mixing  chamber  is  perfectly  dry, 
for  if  any  moisture  collects  between  its  outer  surface  and  the 
inner  surface  of  the  camera  tube,  the  contents  of  the  compart- 
ments may  be  disturbed  and  serious  errors  result.  As  the  open- 
ing in  the  door  of  the  box  is  covered  by  the  hand  with  which 
the  milled  wheel  is  turned,  sufficient  light  to  interfere  with  the 
test  cannot  leak  in  at  this  situation. 

With  a  light-proof  box  of  this  sort  it  is  possible  accurately 
to  carry  on  hemoglobin  estimations  in  the  brightest  daylight, 
which  may  be  entirely  excluded  from  the  instrument,  while  the 
observer's  field  of  vision  is  limited  to  the  two  semicircles  illumi- 
nated by  the  candle  burning  within  the  box. 

With  this  instrument  the  principles  of  Lovi- 
Oliver's     bond's  tintometer  are  applied  to  the  quantitative 
Hemoglobin-  estimation  of  hemoglobin,  the  color  of  a  blood 
ometer.      solution  of  a  definite  strength  being  compared, 
by  light  reflected  from  a  dead  white  surface,  with 
a  series  of  tinted  glass  standards  which  constitute  a  progressive 
color  scale.    Thus,  a  series  of  fixed,  definite  tints  is  provided, 
each  of  which  accurately  corresponds  to  the  specific  color  curve 
of  progressive  dilutions  of  normal  blood,  this  having  been  de- 
termined individually  by  means  of  the  tintometer.    Two  sets 
of  color  standards  have  been  devised:  one  for  daylight  readings 
and  one  for  observations  by  candle-light,  the  latter  being  prefer- 
able on  account  of  the  greater  delicacy  pf  its  readings.  Oliver's 
complete  apparatus  consists  of :  (1)  A  capillary  blood  measure , 
made  of  heavy  glass  tubing,  and  having  a  capacity  of  5  c.mm. 
The  end  to  be  presented  to  the  blood  drop,  in  filling  the 
4 


* 


50       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


measure,  is  tapered  to  a  blunt  point  and  highly  polished.  (2) 
A  mixing  pipette,  provided  with  a  short  rubber  tube  which  fits 
over  the  tapered  end  of  the  blood  measure,  while  rinsing  out 
the  blood  from  the  latter  into  the  (3)  standard  blood  cell,  which, 
when  filled  exactly  to  the  brim  with  distilled  water  in  which  one 
measureful  of  blood  has  been  dissolved,  yields  a  blood  solution 
of  approximately  one  per  cent.  When  filled,  the  cell  is  covered 
with  a  glass  slip  provided  for  this  purpose.  (4)  A  standard  color 
scale,  consisting  of  12  tinted  glass  discs,  mounted  in  two  series, 
and  corresponding  to  hemoglobin  percentages  ranging  from  10 
to  120.  (5)  A  set  of  riders,  or  squares  of  tinted  glass,  used  for 
determining  the  intermediate  degrees  of  color  between  the  deci- 
mals indicated  by  the  fixed  tints  of  the  scale.  For  ordinary  clin- 
ical work  two  riders  are  sufficient,  which,  when  laid  over  the  discs 
of  the  standard  scale,  read  2.5  and  5  degrees  respectively  on  its 
upper  half,  but  double  this  amount  on  the  lower  half.  For  physi- 
ological observations  requiring  readings  in  units  a  set  of  nine 
riders  is  supplied.  (6)  A  collapsible  camera  tube  through  which 
the  color  comparisons  are  made. 

Method  of  Use. — In  making  hemoglobin  estimations  with 
Oliver's  apparatus,  first  the  capillary  measure  is  filled  with  blood 
by  the  method  directed  for  filling  the  pipette  of  the  von  Fleischl 
instrument.  The  rubber  nozle  of  the  mixing  pipette,  previously 
filled  with  distilled  water,  is  then  adjusted  over  the  polished  end  of 
the  blood  measure,  and  the  blood  washed  into  the  standard  cell  by 
forcing  through  the  water,  drop  by  drop.  As  soon  as  all  the 
blood  contained  in  the  bore  of  the  measure  has  been  thus  washed 
out  into  the  cell,  the  rubber  nozle  of  the  pipette  is  removed,  and 
the  handle  of  the  measure  used  as  a  stirrer  to  mix  the  blood 
solution,  more  water  being  added  in  single  drops,  from  time 
to  time,  until  the  cell  is  accurately  filled.  The  blue  cover-glass 
is  then  adjusted,  with  the  result  that,  if  the  cell  has  not  been 
overfilled,  a  small  air-bubble  forms  on  the  surface  of  the  liquid. 
The  blood  cell,  filled  in  this  manner  with  a  blood  solution  of 
definite  strength,  is  now  placed  by  the  side  of  the  standard  scale, 
opposite  the  tinted  disc  to  which  it  corresponds  most  closely, 
the  eye  readily  recognizing  its  approximate  position.  More  accu- 
rate matching  of  the  two  colors  is  made  with  the  aid  of  the 
camera-tube,  the  cell  being  moved  from  disc  to  disc  in  an 
endeavor  to  match  exactly  the  color  of  the  blood  solution  by  one 
of  the  standard  tints  of  the  scale.  If  this  is  successful,  the  hemo- 
globin percentage  indicated  by  the  disc  is  read  off,  and  the  obser- 
vation is  completed.  But  if  it  happens  that  the  tint  of  the  blood 
solution  is  obviously  deeper  than  a  certain  disc,  but  paler  than  the 


ESTIMATION  OF  THE  PERCENTAGE  OF  HEMOGLOBIN.  5 1 

one  immediately  above,  the  cell  is  kept  alongside  the  lower  of  the 
two,  over  which  a  rider  is  adjusted  in  order  to  deepen  its  color, 
while  the  square  of  white  glass  is  placed  over  the  cell,  so  as  to 
compensate  for  the  thickness  of  the  rider.  If,  now,  the  colors 
correspond,  the  final  reading  is  ascertained  by  taking  the  percent- 
age of  the  disc  plus  the  value  of  the  superimposed  rider.  If  the 
color  of  the  blood  solution  is  darker  than  that  of  any  one  of  the 
standard  discs,  but  paler  than  the  disc  plus  a  rider,  the  mean 
average  of  the  two  is  taken  as  the  final  reading;  similarly,  if  the 


Fig.  12. — Method  of  Using  Oliver's  Hemoglobinometer. 


color  of  the  blood  solution  is  darker  than  a  certain  disc  plus  a 
rider,  but  paler  than  the  disc  immediately  above,  the  values  of 
the  two  must  be  averaged.  An  error  of  two  per  cent,  is  un- 
avoidable, even  in  the  hands  of  a  skilful  observer. 

During  the  observation  the  candle  should  be  placed  three  or 
four  inches  from  the  end  of  the  color  scale,  being  adjusted  so  that 
the  flame  is  on  a  line  with  the  opposed  sides  of  the  cell  and  of  the 
scale,  thus  illuminating  both  with  equal  intensity.  The  positions 
of  the  candle  and  of  the  apparatus  are  shown  in  the  accompanying 
illustration   (Fig.  12).    Small-sized  candles,  such  as  are  used 


52       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


for  decorating  Christmas  trees,  furnish  a  flame  of  the  proper  de- 
gree of  brilliancy,  the  candle  of  ordinary  size  giving  too  intense  a 
light.  Total  exclusion  of  daylight  is  not  necessary,  so  that  the 
observation  may  be  made  in  the  corner  of  a  partly  darkened 
room,  as,  for  example,  behind  a  closet  door  or  some  other  similar 
shield  against  direct  rays  of  light. 

Oliver's  hemoglobinometer  is  a  trial  to  the  patience  of  one 
who  has  habitually  used  the  Dare  or  the  von  Fleischl,  and  it 
takes  some  time  to  become  accustomed  to  it  after  having  worked 
with  the  comparatively  simple  color  comparisons  of  other  instru- 
ments. Its  accuracy  is  undeniable,  although  for  clinical  work 
a  simpler  apparatus  is  to  be  preferred. 

This  instrument,  which  for 
Gowers'  many  years  has  been  popular 
Hemoglobin-  in  England  and  is  used  to 
ometer.  some  extent  in  this  country, 
consists  essentially  of  two  small 
flattened  tubes  of  equal  diameter,  which,  when 
in  use,  are  fixed  upright  and  parallel  to  each 
other  in  a  small  wooden  support  furnished  for 
"this  purpose.  One  tube  contains  glycerin  jelly 
colored  with  picrocarmin  to  correspond  to  the 
tint  of  a  i  :  100  solution  of  normal  blood  (or 
20  c.mm.  of  blood  in  2  c.c.  of  water),  this 
being  taken  as  the  standard  with  which  the 
blood  solution  contained  in  the  second  tube 
is  compared.  The  second  tube  is  provided 
with  a  scale  graduated  in  units  from  5  to  120,  each  degree  of 
which  equals  the  volume  of  blood  required  for  the  test.  Twenty 
c.mm.  of  normal  blood,  dissolved  in  sufficient  distilled  water  to 
fill  this  tube  to  the  100  mark  on  the  scale,  give  a  solution  which 
corresponds  to  the  tint  of  the  standard  tube.  The  special  capil- 
lary pipette  used  for  measuring  the  blood  is  graduated  at  10  and 
at  20  c.mm.,  and  fitted  with  a  bit  of  rubber  tubing  and  mouth- 
piece for  filling  it  by  suction. 

Method  of  Use. — The  technic  of  hemoglobin  estimations  with 
Gowers'  apparatus  is  extremely  simple.  Having  made  the  punc- 
ture in  the  usual  manner,  the  blood  is  sucked  up  the  caliber  of 
the  capillary  pipette  until  the  mark  20  is  reached,  and  then  im- 
mediately blown  out  into  the  graduated  tube,  into  which  a  few 
drops  of  distilled  water  have  previously  been  placed,  in  order  to 
insure  instantaneous  solution  of  the  measured  amount  of  blood. 
All  traces  of  blood  which  may  have  adhered  to  the  bore  of  the 
capillary  pipette  are  removed  by  filling  it  several  times  with  water, 


Fig.  13. — Gowers'  Hem- 
oglobinometer. 


ESTIMATION  OF  THE  PERCENTAGE  OF  HEMOGLOBIN. 


53 


the  rinsings  being  added  to  the  mixture  of  blood  and  water  in  the 
tube.  During  the  preceding  steps  the  usual  precautions  must  be 
observed  to  wipe  all  surplus  blood  from  the  outside  of  the  pipette 
before  expelling  its  contents,  and  to  measure  the  blood  rapidly,  so 
as  to  guard  against  errors  arising  from  rapid  clotting.  Distilled 
water  is  now  added,  drop  by  drop,  to  the  mixture  in  the  tube 
until  the  color  of  the  blood  solution  exactly  corresponds  to  that 
of  the  picrocarmin  standard,  the  contents  of  the  tube  being  mixed 
between  each  addition  by  rapidly  reversing  it  two  or  three  times, 
with  its  open  end  closed  by  the  thumb.  The  drop  or  two  of 
liquid  adhering  to  the  thumb  should  be  wiped  off  against  the  wall 
of  the  tube,  so  that  it  may  drain  back  into  the  liquid.  When  the 
tints  of  both  tubes  are  precisely  similar,  the  division  of  the  scale 
to  which  the  diluted  blood  reaches  is  read  off,  to  express  the  per- 
centage of  hemoglobin  in  the  specimen  under  consideration. 

In  comparing  the  colors,  which  is  done  by  daylight,  the  tubes 
should  be  held  against  a  sheet  of  white  paper,  or,  as  suggested 
by  Gowers,  between  the  eye  and  a  window,  and  viewed  at  such 
an  angle  that  their  adjoining  edges  appear  to  overlap,  thus  cutting 
off  the  vertical  streak  of  white  light  visible  between  them  should 
this  precaution  be  neglected.  Owing  to  the  diagonal  position  in 
which  the  two  tubes  are  adjusted  in  their  support,  the  proper 
angle  to  produce  this  effect  may  readily  be  determined. 

The  chief  drawback  to  the  use  of  this  instrument  is  the  likeli- 
hood of  overdiluting  the  blood  after  it  has  been  mixed  in  the 
graduated  tube,  the  occurrence  of  this  accident  necessitating,  of 
course,  a  repetition  of  the  entire  operation.  It  is  not  always 
easy  to  decide  just  when  sufficient  water  has  been  added  to  the 
blood  to  bring  its  color  down  to  that  of  the  standard  tint,  since 
one  must  depend  solely  upon  a  gradual  weakening  of  the  tint  of 
the  blood  solution,  and  this  is  much  more  difficult  than  to  com- 
pare a  definite  blood  color  with  a  sliding  scale  or  with  a  series 
of  discs.  The  instrument  may  be  regarded  as  accurate  within 
two  or  three  per  cent,  for  hemoglobin  percentages  above  ten, 
below  which  figure  it  is  impossible  to  distinguish  a  difference 
between  the  tints  of  the  two  tubes.  This  source  of  error,  how- 
ever, is  too  remote  a  possibility  to  detract  from  the  instrument's 
practical  value.  A  real  source  of  error  in  Gowers'  instrument  is 
the  deterioration  with  age  of  the  picrocarmin  color  standard, 
with  a  consequent  change  in  its  tint.1 

1  Haldane  (Jour.  Physiol.,  1901,  vol.  xxvi,  p.  497)  has  modified  Gowers' 
instrument  by  substituting  for  the  picrocarmin  jelly  a  one  per  cent,  solution  of 
carbonic  oxid  hemoglobin,  which  remains  stable  indefinitely.  Using  Gowers' 
technic,  the  blood  is  first  partly  diluted  and  then  charged  with  illuminating  gas, 


54       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


A  simple  method  of  approximately  determin- 
Tallquist's  ing  hemoglobin  percentages  without  the  aid  of 
Method.  a  special  instrument  has  recently  been  devised 
by  Tallquist,1  the  procedure  consisting,  in  brief, 
in  allowing  a  drop  of  blood  to  soak  into  a  bit  of  filter-paper  and 
comparing  with  the  naked  eye  the  color  strength  of  the  stain 
with  a  series  of  printed  standard  tints  of  known  value.  The  lat- 
ter are  arranged  as  a  scale  of  ten  different  colors,  corresponding 
to  the  colors  of  stains  produced  by  bloods  having  hemoglobin 
values  ranging  from  10  to  100  per  cent.,  the  latter  being  regarded 
as  the  normal.  A  lithographed  copy  of  the  color  standard  ac- 
companies Tallquist's  original  article.  Dealers  in  laboratory 
supplies  also  furnish  a  small  book  containing  the  color  scale  and 
a  supply  of  standard  absorbent  paper.  The  test  is  made  in  the 
following  manner:  A  drop  of  blood,  large  enough  to  make  a 
stain  about  5  or  6  mm.  in  diameter,  is  caught  in  the  center  of  a 
piece  of  white  filter-paper,  care  being  taken  in  collecting  it  to 
apply  the  paper  to  the  exuding  drop  in  such  a  manner  that  the 
blood  soaks  in  very  slowly,  and  thus  produces  a  stain  which  is 
evenly  colored  throughout.  Perfectly  white  filter-paper,  having 
a  smooth  surface  and  of  a  thickness  corresponding  to  about  55 
leaves  to  the  centimeter,  should  be  used  for  the  test.  The  blood 
stain  thus  made  is  pressed  lightly  against  a  pad  of  filter-paper, 
and  then  compared,  by  direct  daylight,  with  the  series  of  standard 
tints,  the  figure  opposite  to  the  tint  which  the  stain  most  accurately 
matches  being  read  off,  to  indicate  the  percentage  of  hemoglobin 
in  the  specimen  under  examination.  The  comparison  must  be 
made  immediately  after  the  stain  loses  its  humid  gloss,  since 
blood  soon  changes  its  color  after  exposure  to  the  air. 

This  direct  method  of  hemoglobin  testing  is,  of  course,  only 
approximate,  at  the  best,  and  cannot  be  expected  to  furnish  re- 
sults comparable  in  point  of  accuracy  with  those  to  be  obtained 
by  any  of  the  instruments  just  described.  It  may,  however,  be 
employed  to  excellent  advantage  when  a  hemoglobinometer  is 

by  means  of  a  special  fitting  to  be  attached  to  a  gas-burner.  The  oxyhemoglobin 
of  the  blood  is  thus  converted  into  carbonic  oxid  hemoglobin,  the  color  of  which 
is  comparable  to  that  of  the  standard  solution.  After  having  been  charged  with 
gas,  the  blood  is  mixed  by  repeatedly  inverting  the  tube,  the  open  end  of  which 
is  closed  by  the  thumb,  after  which  the  dilution  is  proceeded  with  until  the  colors 
match,  when  the  final  reading  is  made.  The  inventor's  claims  for  the  accuracy 
of  his  instrument  have  been  substantiated  by  Horder  (Lancet,  1903,  vol.  i, 
p.  1305).  In  ten  estimates  by  different  observers  it  was  determined  that  the 
possible  errors  with  Haldane's  instrument  averaged  1.9  per  cent.,  and  with  the 
hemometer,  4.25  per  cent.  Haldane's  device,  despite  its  accuracy,  obviously  is 
better  adapted  to  physiological  research  work  than  to  clinical  hematology. 

1  St.  Paul  Med.  Jour.,  1900,  vol.  ii,  p.  291. 


COUNTING  THE  ERYTHROCYTES  AND  LEUCOCYTES.  55 

not  at  hand,  or  in  certain  cases  in  which  only  a  rough  estimate  of 
the  amount  of  coloring  matter  of  the  blood  is  sought.  Tall- 
quist,  who  has  tested  his  method,  under  the  control  of  the  he- 
mometer,  in  his  clinic  at  Helsingfors,  claims  that  the  limit  of  error 
generally  does  not  exceed  ten  per  cent. 

Here  may  be  mentioned  Haig's  blood  decimal  card,  devised 
for  roughly  estimating  the  color  index  of  the  blood.  It  consists 
of  a  series  of  four  different  colors,  scaled  0.80,  0.60,  0.40,  and 
0.20,  respectively.  By  matching  one  of  these  colors  with  the 
color  of  the  patient's  gums  or  tongue  an  approximate  idea  of  the 
individual's  color  index  is  obtained.  Haig's  device  may  serve 
for  a  hurried  examination,  but  it  is  obviously  too  crude  to  give 
accurate  results. 

III.    COUNTING    THE    ERYTHROCYTES   AND  THE 
LEUCOCYTES. 

Of  the  various  instruments  used  for  count- 
Methods.  ing  the  blood  corpuscles,  the  hemocytometers  de- 
vised by  Thoma  and  by  Gowers  are  most  gener- 
ally employed  at  the  present  time,  the  former  being  used  almost 
to  the  exclusion  of  the  latter  everywhere  except  in  England, 
where  Gowers'  apparatus  has  many  firm  adherents.  Durham, 
by  adapting  and  modifying  a  number  of  the  details  of  the  older 
instruments,  has  succeeded  in  devising  an  improved  form  of  hemo- 
cytometer  which  possesses  many  advantages  over  the  original 
models,  being  of  simple  construction,  accurate,  and  comparatively 
inexpensive.  The  method  of  making  the  estimate,  which  is  es- 
sentially the  same  with  all  three  of  these  instruments,  consists, 
briefly,  in  first  diluting  the  fresh  blood  in  definite  proportions  with 
some  indifferent  preservative  fluid,  and  in  then  counting,  under 
the  microscope,  the  number  of  corpuscles  in  a  drop  of  the  diluted 
blood,  the  latter  being  contained  in  a  small  glass  cell  on  the  floor 
of  which  is  ruled  a  series  of  micrometer  squares  of  certain  dimen- 
sions. The  cubic  contents  of  the  cell  and  the  degree  of  the  blood 
dilution  being  known,  the  number  of  corpuscles  counted  in  any 
given  number  of  these  squares  may  be  taken  as  a  basis  for  cal- 
culating the  total  count  of  corpuscles  to  the  cubic  millimeter 
of  blood. 

Strong  and  Seligmann  dispense  with  a  special  counting  cham- 
ber, and  enumerate  the  cells  in  a  measured  quantity  of  blood 
diluted  in  definite  proportions  with  a  diluent-stain  and  mounted 
as  a  permanent  dry  specimen. 

Oliver  has  devised  an  instrument  with  which  the  number  of 


56       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

erythrocytes  may  be  estimated  by  means  of  their  optical  effect, 
without  the  use  of  the  microscope. 

Diluting  fluids  for  use  with  the  hemocytom- 
Diluting     eters  of  Thoma,  Gowers,  and  Durham  should 
Fluids.       be  of  such  a  composition  that  when  mixed  with 
the  fresh  blood  they  preserve  unaltered  the  form 
of  the  corpuscles.    This  requirement  being  met,  the  examiner 
may  choose  from  the  numerous  formulas  in  current  use  the  one 
which  best  suits  his  individual  preference.    Among  the  most  sat- 
isfactory solutions  used  for  this  purpose  the  following  may  be 
mentioned : 


TOISSON'S  SOLUTION. 

Methyl-violet,  5  B   0.025 

Sodium  chlorid   1.0 

Sodium  sulphate   8.0 

Neutral  glycerin    30.0 

Distilled  water  160.0 

SHERRINGTON'S  SOLUTION. 

Methylene-blue   0.1 

Sodium  chlorid   1.2 

Neutral  potassium  oxalate  - —  1.2 

Distilled  water   300.0 


For  general  clinical  work  no  better  formulas  have  ever  been 
suggested  than  the  preceding  two.  Both  solutions  act  as  excel- 
lent preservative  fluids,  and  each  contains  just  sufficient  quantity 
of  a  basic  anilin  dye  to  stain  the  leucocytes  with  great  distinct- 
ness, so  that  they  may  readily  be  differentiated  from  the  erythro- 
cytes, which  remain  uncolored. 

HAYEM'S  SOLUTION. 


Mercuric  chlorid   0.25 

Sodium  chlorid   0.5 

Sodium  sulphate   2.5 

Distilled  water  100.0 


Oliver  specifies  this  solution  as  the  diluent  invariably  to  be 
employed  with  his  instrument,  but  it  may  be  used  also  with  the 
other  forms  of  hemocytometers,  although  with  less  satisfaction 
than  the  formulas  first  mentioned. 

Among  the  simpler  diluting  fluids,  all  of  which  are  depend- 
able, are  solutions  in  distilled  water  of  common  salt  (0.7  per  cent.), 
of  potassium  bichromate  (2.5  per  cent.),  and  of  sodium  sulphate 
(5  per  cent.),  to  any  of  which  about  0.5  per  cent,  of  an  alcoholic 
solution  of  methyl-violet  may  be  added,  in  order  to  stain  the 
leucocytes,  and  thus  to  facilitate  the  counting. 


COUNTING  THE  ERYTHROCYTES  AND  LEUCOCYTES.  6 1 

shaken  for  about  half  a  minute.  By  the  above  steps  a  mixture 
is  made  in  which  the  proportion  of  blood  to  diluent  is  i  :  200,  a 
degree  of  dilution  with  which  it  is  most  convenient  to  work  in 
the  great  majority  of  instances.  For  two  reasons  a  1  :  200,  rather 
than  a  1:100,  dilution  is  to  be  preferred  in  routine  work:  (1) 
If,  as  not  infrequently  happens,  the  blood  column  is  accidentally 
drawn  up  the  tube  beyond  the  mark  0.5  in  an  attempt  exactly 
to  reach  this  gradation,  it  is  a  simple  matter  to  correct  the  error 
by  gently  blowing  or  shaking  the  blood  column  down  to  the 


Fig.  18. — Method  of  Filling  the  Capillary  Tube  of  the  Thoma-Zeiss  Hemocytometer 

with  Blood. 

proper  level;  whereas,  in  attempting  to  make  a  1  :  100  dilution, 
should  .the  mark  1  be  exceeded,  the  blood  column  will  almost 
surely  escape  into  the  bulb,  whence  it  cannot  be  blown  back  again 
into  the  capillary  tube,  thus  necessitating  a  repetition  of  the 
whole  operation  with  a  fresh  drop  after  having  cleaned  and  dried 
the  erythrocytometer.  (2)  It  is  easy  to  count  the  corpuscles 
in  a  1 :  200  dilution,  since  the  surface  of  each  ruled  square  of  the 
counting  chamber  is,  as  a  rule,  occupied  by  not  more  than  half 
a  dozen  cells;  on  the  contrary,  in  a  1  :  100  dilution,  except  in 
an  occasional  instance  in  which  there  is  a  striking  paucity  of  cells, 


62       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

the  field  may  be  so  overcrowded  with  corpuscles  that  their  enu- 
meration is  difficult  and  often  inaccurate. 

The  next  step  is  to  place  a  drop  of  the  diluted  blood  in  the 
counting  chamber,  preparatory  to  counting  the  corpuscles  under 
the  microscope.  The  unmixed  diluting  fluid  in  the  lower  portion 
of  the  capillary  tube  is  first  expelled,  by  blowing  out  four  or  five 
drops,  after  which  the  point  of  the  pipette  is  dried  with  a  soft 
cloth  and  a  small  drop  of  the  blood  mixture  is  allowed  to  fall, 
by  force  of  gravity,  exactly  in  the  center  of  the  surface  of  the 
ruled  disc.  The  cover-glass  is  then  immediately  placed  in  posi- 
tion, and  the  slide  left  undisturbed  for  several  minutes,  so  that 
the  corpuscles  may  settle.  The  drop  placed  on  the  disc  should 
be  of  sufficient  size  to  occupy  only  its  central  portion,  the  object 
being  to  use  just  enough  of  the  blood  mixture  to  cover  the  ruled 
area  and  exactly  to  fill  in  the  vertical  space  between  the  surfaces 
of  the  disc  and  cover-glass  when  the  latter  is  placed  in  position. 
If  the  drop  contains  air-bubbles,  or  if  it  is  so  large  that  it  over- 
flows into  the  gutter  and  perhaps  finds  its  way  between  the  cover- 
glass  and  the  glass  plate  beneath,  errors  will  result,  so  that  in  the 
event  of  either  of  these  accidents  the  procedure  must  be  repeated 
with  another  drop,  after  having  cleaned  and  dried  the  cover-glass 
and  the  counting  chamber.  Water,  and  not  alcohol  or  xylol,  is 
to  be  used  for  this  purpose,  since  the  repeated  use  of  chemicals 
will  soon  dissolve  the  cement  which  fixes  the  disc  to  the  counting 
chamber.  In  repeating  the  operation  the  original  technic  must 
be  rigidly  followed — i.  e.,  the  erythrocytometer  must  be  briskly 
shaken  for  half  a  minute  or  so,  and  the  contents  of  its  capillary 
stem  blown  out,  before  placing  the  new  drop  in  the  counting 
chamber. 

In  a  properly  prepared  slide  concentric  rings  of  color — New- 
ton's rings — may  be  seen  at  the  points  of  contact  between  the 
cover-glass  and  the  underlying  glass  plate.  If  these  rings  are  in- 
visible, or  if  they  do  not  appear  when  pressure  is  made  upon  the 
cover-glass,  it  is  a  sign  that  the  contact  between  the  two  glass 
surfaces  is  not  true,  this  being  due  to  the  presence  of  particles  of 
dust  or  of  moisture  beneath  the  cover- glass.  Inasmuch  as  this 
may  seriously  affect  the  correctness  of  the  count,  it  is  a  safe  rule 
invariably  to  reject  a  slide  in  which  these  color  rings  are  not  visible. 

As  soon  as  sufficient  time  has  elapsed  for  the  corpuscles  to  sink 
to  the  bottom  of  the  counting  chamber — about  five  minutes — the 
slide  is  transferred  to  the  stage  of  the  microscope,  which  should  not 
be  inclined,  for  fear  of  disturbing  the  uniform  distribution  of  the 
cells.  The  field  is  first  brought  into  focus  with  a  low-power  objec- 
tive (a  No.  3  objective  of  Leitz,  for  example),  and  the  slide  moved 


COUNTING  THE  ERYTHROCYTES  AND  LEUCOCYTES. 


63 


across  the  stage  until  the  extreme  upper  left-hand  corner  of  the 
group  of  small  ruled  squares  is  brought  into  view,  when  a  higher 
power,  to  be  used  in  counting,  is  substituted.  For  this  purpose 
the  writer  is  accustomed  to  use  a  Leitz  No.  6  objective  and  No.  4 
ocular,  which  lenses,  with  a  tube  length  of  155  mm.,  cut  off  a 
field  occupied  by  a  block  of  25  small  squares. 

As  a  basis  for  the  final  calculation,  the  erythrocytes  in  400 
small  squares,  or  the  entire  ruled  surface  of  the  old-style  disc, 
should  be  counted,  preferably  by  going  over  two  groups  of  200 
squares  each  in  two  different  drops,  rather  than  by  taking  the  en- 
tire 400  squares  in  a  single  specimen.    By  following  this  plan  the 


Fig.  19. — Plan  of  Counting  the  Erythrocytes. 
The  small  squares  are  examined  in  the  order  indicated  by  the  arrow,  successive  blocks  of  25 
squares  being  covered  until  the  required  number  of  cells  has  been  counted. 

count  of  one  drop  may  be  controlled  by  the  count  of  the  other, 
and  any  discrepancy  between  the  two  discovered,  for  if  the  dif- 
ference in  the  counts  is  striking,  a  third  group  of  200  squares 
must  be  examined  in  an  additional  drop,  and  an  average  taken 
of  the  two  counts  which  most  closely  correspond. 

In  order  to  simplify  the  process  of  counting,  some  routine 
method  of  examining  the  ruled  area,  such  as  the  following,  should 
be  adopted:  Beginning  at  the  upper  left-hand  corner  of  the  ruled 
disc,  the  corpuscles  in  the  first  100  small  squares  are  counted, 
the  slide  being  moved  from  above  downward,  preferably  by  the 
aid  of  a  mechanical  stage,  as  the  successive  groups  of  squares  are 


64       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

covered.  By  employing  the  magnification  to  which  reference  has 
just  been  made,  three  shifts  of  the  slide  are  sufficient  to  bring 
into  the  field  the  requisite  number  of  squares  in  blocks  of  25 
each.  Examining  each  small  square  in  succession,  proceed  from 
left  to  right  along  one  row  of  five,  then  drop  to  the  next  row  and 
count  from  right  to  left,  and  continue  in  the  manner  illustrated 
by  the  diagram  (Fig.  19)  until  all  the  erythrocytes  in  the  first 
group  of  100  squares  have  been  counted,  the  totals  of  each  block 
of  25  squares  being  noted  as  they  are  completed.  To  avoid  repe- 
tition in  counting  it  is  necessary  to  include  in  the  total  all  the  cor- 
puscles which  touch  the  upper  and  left  boundary  lines,  and  to 
disregard  those  which  touch  the  lower  and  right  boundaries.  A 
second  group  of  100  squares,  not  immediately  adjacent  to  the 
first,  is  then  inspected  in  a  similar  manner,  after  which  the  cover- 
glass  and  counting  chamber  are  washed  with  water  and  dried,  and 
the  operation  repeated  with  a  second  drop.  Thus  the  400  squares 
are  covered  by  examining  16  blocks  of  25  squares  each — 8  in  the 
first  and  8  in  the  second  drop  of  diluted  blood.  In  a  1 : 200 
dilution  of  normal  blood  this  involves  the  counting  of  approxi- 
mately from  2400  to  2800  erythrocytes,  and  gives  results  which 
are  accurate  within  one  and  one-half  per  cent. 

To  calculate  the  number  of  erythrocytes  to  the  cubic  milli- 
meter of  blood  the  following  formula  is  employed : 

Number  of  eryth-  x  Degree  of  dilu-  ^  Cubic  contents  of  each      Total  num- 

rocytes  counted         lion  (200)  square  (4000)   _  oer  0j  erythro- 

Number  of  squares  counted  (400)  cytes  per  c.mm. 

For  example,  supposing  that  in  the  400  squares  of  a  1  :  200 
blood  dilution  a  total  of  2500  erythrocytes  is  counted,  the  cal- 
culation is  made  thus : 

(a)  2500  X  200  X  4000  =  5jooo,ooo  erythrocytes  per  c.mm. 

400 

{b)       2500X2000       =  5,000,000  erythrocytes  per  c.mm. 

Counting  the  Leucocytes. — The  leucocytes  may  be  counted  by 
two  different  methods:  (a)  With  the  erythrocytometer,  in  the 
same  drop  of  diluted^ blood  in  which  the  erythrocytes  are  esti- 
mated; or  (b)  with  the  special  leucocytometer,  as  a  separate  pro- 
cedure. Of  the  two  methods,  the  former  is  greatly  to  be  preferred, 
since  it  is  fully  as  accurate  and  much  more  convenient  and  time- 
saving  than  the  latter.  Furthermore,  there  is  an  undoubted  ad- 
vantage in  counting  both  the  red  and  the  white  corpuscles  in  the 
same  drop  of  the  blood  dilution. 

(a)  If  the  leucocytes  are  counted  with  the  erythrocytometer, 
the  same  technic  is  followed  as  in  determining  the  number  of 


COUNTING  THE  ERYTHROCYTES  AND  LEUCOCYTES.  65 


erythrocytes,  except  that  a  much  larger  area  of  the  counting 
chamber  must  be  examined,  owing  to  the  comparatively  small 
number  of  leucocytes  contained  in  the  i  :  200  blood  mixture. 
It  is  necessary,  for  the  sake  of  accuracy,  to  count  the  leucocytes 
in  the  entire  space  inclosed  by  Zappert's  ruling,  and  to  repeat  the 
count  in  a  second  drop,  making  an  area  equal  to  eighteen  times 
the  ruled  space  of  the  old-style  counting  chamber  to  be  examined. 
If  the  totals  of  both  counts  are  approximately  the  same,  their 
combined  figures,  representing  the  corpuscles  found  in  a  space 
corresponding  to  7200  of  the  small  ruled  squares,  are  taken  as  a 
basis  for  the  final  estimate;  but  if  these  totals  differ  widely,  a 
third  drop  is  to  be  examined  in  the  same  manner,  and,  as  in 
counting  the  erythrocytes,  an  average  taken  of  the  two  totals 
which  are  nearest  alike.  Since  in  normal  blood,  in  a  1  :  200 
dilution,  each  block  of  400  small  squares  contains  from  3  to  6 
leucocytes,  the  examination  of  the  above-mentioned  area  of  the 
counting  chamber  involves  the  counting  of  approximately  from 
54  to  108  of  these  cells — an  operation  which,  practically,  is  not 
nearly  so  laborious  as  it  appears  from  the  description,  being 
easily  completed  within  ten  or  fifteen  minutes  in  most  cases.1 

As  an  example  of  the  method  of  calculating  the  final  estimate, 
supposing  that  90  leucocytes  have  been  counted  in  the  area  equal 
to  7200  small  squares,  the  blood  dilution  being  1 :  200,  this  for- 
mula is  employed: 

90  X  200  X  4000  -r-  7200  =  10,000  leucocytes  per  c.mm. 

If  the  old-style  counting  chamber  is  used,  the  leucocytes  in  the 
unruled  portion  of  the  disc  outside  of  the  central  block  of  400 
squares  may  be  counted  with  the  aid  of  an  eye- 
piece diaphragm,  which,  when  adjusted  inside 
the  tube  of  the  ocular,  cuts  off  a  field  exactly 
the  size  of  100  small  squares  (Fig.  20).  A 
black  metal  or  cardboard  disc  having  a  central 
aperture  of  the  proper  size  will  answer  just  as 
well  for  this  purpose  as  the  more  expensive 
and  elaborate  mechanical  eye-piece  devised  by 
Ehrlich,  which  is  provided  with  a  diaphrag  m  Diaphragm. 
having  a  square  opening  the  size  of  which  is 
regulated  by  a  small  lever.  Having  first  counted  all  the  leuco- 
cytes in  the  400  small  squares,  the  cells  are  then  counted  in 
32  of  the  diaphragm-fields  outside  the  latter,  in  order  to  cover 

1  Should  the  leucocytes  be  decidedly  increased,  it  is  unnecessary  to  cover  so 
large  a  number  of  squares.    One  hundred  cells  taken  as  a  basis  for  the  calculation 
will  give  an  accurate  estimate. 
5 


66       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

an  area  of  the  disc  corresponding  to  the  entire  ruled  surface  of  the 
Zappert  counting  chamber.  This  operation  having  been  repeated 
in  a  second  drop,  the  totals  of  both  counts  are  taken  as  the  basis 
for  the  final  calculation,  which  is  made  in  the  manner  already 
described. 

If  one  happens  to  have  neither  an  eye-piece  diaphragm  nor 
a  Zappert  counting  chamber,  the  following  method  of  calculat: 
ing  the  cubic  contents  of  the  portions  of  the  disc  outside  the 
ruled  area  may  be  adopted,  as  advised  by  Stengel.1  Using,  for 
example,  a  -J-inch  objective  and  a  i-inch  ocular,  the  ruled  lines 
are  brought  into  focus,  and  the  tube  of  the  microscope  drawn 
out  until  one  of  the  parallel  lines  of  the  ruled  disc  exactly  coin- 
cides with  either  boundary  of  the  field  of  vision.  Assuming  that  8 
of  these  parallel  columns,  each  mm.  in  width,  are  included 
in  the  visual  field,  the  diameter  of  the  latter  is  therefore  -^j-,  or  f 
mm.,  and  the  radius  one-half  of  this  figure,  T\,  or  |  mm.  The 
area  of  the  field  may  then  be  readily  determined  by  multiplying 
the  square  of  its  radius  by  3. 141 6.  Its  cubic  contents  are 
obtained  by  also  multiplying  by  ^  mm.,  the  formula  being: 

I  X  I  X  jo  X  3.1416  =  0.0125664,  cubic  contents  of  the  visual  field. 

Having  in  this  manner  ascertained  the  cubic  contents  of  each 
field  of  vision,  the  final  calculation  of  the  number  of  leucocytes 
to  the  c.mm.  of  undiluted  blood  is  made  by  multiplying  the  total 
number  of  these  cells  found  in  a  definite  number  of  fields  (for  in- 
stance, 50)  by  the  degree  of  dilution  (usually  1 :  200),  and  then  by 
dividing  the  cubic  contents  of  each  field  (0.0125664)  multiplied 
by  the  number  of  fields  examined.  The  formula  for  this  calcula- 
tion is: 

Total  number  of  leucocytes  counted  X  Degree  of  dilution  ~ 
Cubic  contents  of  visual  field  X  Number  of  fields  examined  = 
Total  number  of  leucocytes  per  c.mm. 

For  example,  in  a  1  :  200  blood  dilution  a  total  of  30  leucocytes 
is  noted  in  fifty  fields,  each  having  a  cubic  contents  of  0.0125664, 
since  they  individually  include  8  parallel  columns  of  the  ruled  disc : 

(30  X  200)  — r~  (0.0125664  X  50)  =  9550  leucocytes  per  c.mm. 

(b)  If  the  special  leucocytometer  is  used  for  counting  the  leu- 
cocytes, a  0.3  per  cent,  aqueous  solution  of  glacial  acetic  acid 
must  be  employed  as  a  diluent,  in  order  to  render  invisible  the 
erythrocytes  and  at  the  same  time  to  make  the  leucocytes  appear 


1  "Twentieth  Century  Practice  of  Medicine,"  New  York,  1896,  vol.  vii,  p.  271. 


COUNTING  THE  ERYTHROCYTES  AND  LEUCOCYTES.  67 

more  conspicuously  in  the  field.  A  i  :  10  dilution  is  made  by 
drawing  the  blood  up  the  capillary  tube  of  the  instrument  until 
the  mark  i  is  reached,  and  by  then  adding  the  diluent  until  the 
mixture  reaches  the  mark  n.  The  leucocytes  are  then  counted 
in  an  area  of  the  counting  chamber  equal  to  800  of  the  small 
squares  (preferably  by  examining  400  squares  in  two  separate 
drops),  and  the  calculation  made  according  to  the  method  pre- 
viously described.  For  instance,  if  in  a  given  case  130  leucocytes 
were  counted  in  800  squares,  the  estimate  would  be  made  as 
follows : 

130  X  4000  X  10  -r-  800  =  6500  leucocytes  per  c.mm. 

The  chief  objection  to  this  method  of  leucocyte  counting  lies 
in  the  difficulty  in  distinguishing  the  cells,  owing  to  the  unavoid- 


Fig.  21. — Expelling  Contents  of  Erythrocytometer. 
By  twisting  the  rubber  suction  tube  into  a  tight  spiral  rope  the  fluid  in  the  bore  of  the  pipette  may 
be  forcibly  expelled  in  a  fine  jet. 

able  presence  in  the  field  of  masses  of  granular  debris  resulting 
from  the  action  of  the  acetic  acid  solution  upon  the  erythrocytes. 
For  this  reason,  if  for  no  other,  it  seems  advisable  to  dispense 
with  the  leucocytometer,  and  to  make  the  count  of  both  red  and 
white  corpuscles  with  the  erythrocytometer  in  the  same  drop. 

Cleaning  the  Pipette. — As  soon  as  the  count  has  been  finished, 
the  pipette  should  be  carefully  cleaned  and  dried.  Having  first 
expelled  what  remains  of  the  blood  dilution,  the  instrument  is 
rinsed  out,  first  with  distilled  water  and  then  with  a  mixture  of 
equal  parts  of  absolute  alconol  and  ether,  the  latter  being  used  to 
remove  all  traces  of  the  dye,  in  case  either  Toisson's  or  Sherring- 
ton's solution  has  been  employed  as  a  diluent,  as  well  as  to  dry 
the  interior  of  the  tube.  The  pipette,  while  it  may  be  filled  with 
a  fluid  by  suction,  should  not  be  emptied  by  blowing  through  it, 
for  if  this  is  done,  a  certain  amount  of  moisture  from  the  breath 
unavoidably  becomes  deposited  in  its  lumen.    Its  contents  may  be 


68       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


expelled  in  the  form  of  a  fine  jet,  simply  by  twisting  the  rubber  suc- 
tion tube  into  a  tight  spiral  rope,  as  shown  in  the  illustration  (Fig. 
21).  ^  When  the  interior  of  the  instrument  is  perfectly  clean,  it 
is  dried  by  forcing  through  it  a  current  of  air  by  means  of  a 
rubber  atomizer  bulb,  or  an  ordinary  bicycle-pump,  until  the  glass 
bead  no  longer  clings  to  the  wall  of  the  bulbous  expansion,  as  it 
will  as  long  as  the  slightest  trace  of  moisture  remains.1 

A  new  form  of  hemocytometer  has  been 
Durham's  Hem-  recently  designed  by  Durham,  who  has  em- 
ocytometer.  bodied  in  this  device  the  principles  of  the  older 
instruments,  together  with  the  substitution  of  a 
self-measuring  pipette  designed  to  overcome  the  sources  of  error 
which  may  occur  in  making  blood  dilutions  with  a  suction  pipette. 
Durham's  instrument,  which  appears  to  be  a  valuable  improve- 
ment over  other  forms  of  blood-counting  apparatus,  consists  of 
the  following  parts: 

i.  Several  capillary  pipettes  of  the  Oliver  type,  each  mounted 


Fig.  22. — Cross-section  of  Durham's  Blood  Pipette. 
>e;  N,  rubber  nipple;  p,  lateral  perforation  in  nipple;  c,  cork  in  which  a  capillary  pipette 
is  fitted. 


in  a  glass  tube,  provided  with  a  rubber  nipple  having  a  lateral 
perforation.    The  capacity  of  the  pipettes  is  5  and  10  c.mm. 

2.  A  number  of  mixing  vessels,  each  consisting  of  a  small  glass 
test-tube,  graduated  from  1  and  for  0.5  c.c.  of  fluid.  The  tubes 
holding  1  c.c.  measure  2f  x  T\  in.,  and  those  holding  0.5  c.c, 
2|  X  I  in.  One  or  more  glass  beads  are  shaken  about  in  the 
tube  to  mix  the  blood  and  the  diluting  fluid. 

3.  A  number  of  graduated  pipettes  for  measuring  the  diluting 
fluid,  of  1  and  0.5  c.c.  capacity,  marked  at  995  and  990  c.mm. 
and  at  495  and  490  c.mm.,  respectively.  Used  with  the  appro- 
priate capillary  pipette,  dilutions  of  1:200,  i:ico,  and  1:50 
may  be  obtained. 

4.  A  counting  chamber  of  the  Thoma-Zeiss  pattern. 

Method  0]  Use. — Having  placed  in  one  of  the  mixing  vessels 
some  of  the  diluting  fluid,  the  quantity  of  which  is  measured  with 

1  A  0.1  per  cent,  solution  of  pepsin  in  one  per  cent,  hydrochloric  acid  is  useful 
for  removing  any  bits  of  clotted  blood  which  may  adhere  to  the  caliber  of  the 
instrument. 


COUNTING  THE  ERYTHROCYTES  AND  LEUCOCYTES.  69 

one  of  the  graduated  pipettes  according  to  the  dilution  desired,  the 
capillary  pipette  is  filled  with  blood  by  touching  it  lightly  to  the 
blood  drop  as  it  flows  from  the  puncture.  All  traces  of  blood  are 
then  removed  from  the  outside  of  the  pipette,  the  contents  of  which 
are  now  expelled  into  the  fluid  contained  in  the  mixing  vessel. 
This  is  accomplished  by  inserting  the  pipette  into  the  latter,  keep- 
ing its  point  about  half  an  inch  above  the  level  of  the  diluting  fluid, 
and  by  then  rotating  it  between  the  thumb  and  forefinger  so  that 
the  lateral  perforation  is  brought  under  the  ball  of  the  thumb; 
the  nipple  is  now  squeezed  gently,  and,  continuing  the  pressure, 
the  pipette  is  rotated  back  so  that  the  perforation  is  free  again. 
In  this  manner  the  blood  is  forced  from  the  pipette  but  is  not 
sucked  back.  The  blood  remaining  in  the  pipette  is  now  com- 
pletely washed  away  by  thrusting  its  point  into  the  diluting  fluid, 
this  at  once  filling  its  caliber,  by  capillarity.  Withdrawing  the 
pipette  from  the  fluid,  the  rotation  and  pressure  of  the  nipple  are 
repeated,  the  capillary  tube  being  thus  rinsed  out  several  times  in 
order  to  remove  completely  all  the  blood  clinging  to  its  interior. 

The  blood  and  the  diluting  fluid  are  now  mixed  by  briskly  ro- 
tating the  mixing  vessel  between  the  opposed  hands,  so  that  the 
tumbling  about  of  the  glass  beads  in  the  vessel  may  thoroughly 
distribute  the  cellular  elements  through  the  fluid.  When  the 
mixing  is  completed,  a  drop  of  the  fluid  is  transferred  to  the 
counting  chamber,  and  the  corpuscles  counted  under  the  micro- 
scope in  the  usual  manner. 

Durham's  device  makes  it  possible  for  the  unskilled  to  measure 
accurately  the  desired  volumes  of  blood  and  diluting  fluid,  and 
largely  eliminates  the  errors  which  are  likely  to  occur  in  sucking 
up  the  blood  and  the  diluent  with  either  the  Thoma-Zeiss  or 
the  Gowers  hemocytometer.  The  ease  and  thoroughness  with 
which  the  capillary  blood  pipette  may  be  cleaned  are  also  ad- 
vantages, this  being  done  by  passing  through  its  caliber  a  piece  of 
darning-cotton,  dry  or  soaked  in  ether,  by  means  of  a  needle. 
Comparative  observations  made  with  the  Thoma-Zeiss  hemocy- 
tometer have  shown  that  the  readings  of  the  two  instruments  are 
practically  identical. 

In  this  form  of  hemocytometer  the  blood  and 
Gowers'  Hem-  the  diluting  fluid  are  each  measured  in  a  separate 
ocytometer.  pipette,  and  deposited  in  a  small  receptacle,  in 
which  they  are  mixed,  a  small  portion  of  the  mix- 
ture then  being  placed  in  a  counting  chamber  and  the  number  of 
corpuscles  counted  under  the  microscope.    Gowers  prefers  to  use 
as  a  diluent  an  aqueous  solution  of  sodium  sulphate  having  a 
specific  gravity  of  1.025,  Dut  Toisson's  solution,  or  any  of  the 


70       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

other  diluting  fluids  previously  mentioned,  will  prove  satisfactory. 
The  instrument  comprises  five  working  parts,  as  follows: 

1.  A  pipette,  graduated  to  hold  a  volume  of  995  c.mm.,  for 
measuring  the  diluting  fluid. 

2.  A  capillary  pipette,  graduated  to  hold  a  volume  of  5  c.mm., 
for  measuring  the  blood. 

3.  A  small  glass  mixing  jar,  in  which  the  dilution  of  the  blood 
is  made. 

4.  A  glass  stirring  rod,  for  mixing  the  blood  and  the  diluent 
in  the  jar. 

5.  A  counting  chamber,  consisting  of  a  glass  slide  mounted  on 
a  brass  plate,  and  containing  a  cell  \  mm.  in  depth,  the  floor  of 
the  cell  being  divided  by  cross-rulings  into  squares  the  sides  of 
which  measure  y7  mm.  When  a  cover-glass  is  fitted  over  this 
cell,  being  retained  in  position  by  means  of  a  pair  of  clips  attached 
to  either  end  of  the  brass  plate,  the  cubic  contents  of  the  space 
overlying  each  square  measure  c.mm. 

Method  0}  Use. — In  using  the  instrument  995  c.mm.  of  the 
diluting  solution  are  first  measured  by  means  of  the  larger  pip- 
ette and  blown  out  into  the  mixing  jar.  The  latter  must  be 
perfectly  clean  and  absolutely  free  from  moisture  before  it  is 
used,  in  order  to  avoid  errors  in  the  count.  Now,  using  the 
capillary  blood  pipette,  5  c.mm.  of  blood  are  secured  from  the 
puncture,  and  immediately  added  to  the  diluent  contained  in  the 
jar.  The  blood  and  the  diluent  are  then  thoroughly  mixed,  by 
rapidly  stirring  the  solution  with  the  glass  rod.  The  dilution  thus 
made  is  in  the  proportion  of  1 :  200  of  blood  to  diluent.  As 
soon  as  the  mixture  is  completed,  a  small  drop  of  the  solution  is 
transferred  to  the  center  of  the  cell  in  the  middle  of  the  counting 
chamber,  the  small  end  of  the  glass  rod  being  used  for  this  pur- 
pose, after  which  the  cover-glass  is  gently  placed  in  position,  and 
the  clips  adjusted  so  as  to  hold  it  in  place.  The  counting  cham- 
ber may  then  be  placed  upon  the  stage  of  the  microscope,  and 
the  corpuscles  overlying  the  ruled  portion  of  the  cell  brought 
into  focus  with  a  low-power  objective. 

It  is  necessary  to  use  a  small  drop  of  the  diluted  blood,  and 
to  place  it  exactly  in  the  center  of  the  block  of  ruled  squares, 
otherwise  the  fluid  may  flow  toward  the  walls  of  the  cell,  alter- 
ing its  volume  and  making  it  necessary  to  reject  the  specimen 
and  to  prepare  a  new  drop,  after  thoroughly  cleaning  and  drying 
the  cell,  and  again  stirring  the  blood  solution. 

The  corpuscles  having  settled  to  the  bottom  of  the  cell,  their 
number  in  a  given  number  of  squares  is  noted,  and  the  final  cal- 
culation made  according  to  the  formula: 


COUNTING  THE  ERYTHROCYTES  AND  LEUCOCYTES. 


71 


Number  0}  Number  of       TM  q}  CQf_ 

corpuscles  X  200  X  500  -     squares     =  ^     r  c>ww> 

counted  counted  1  r 

In  counting  the  erythrocytes  at  least  20  squares  of  the  count- 
ing chamber  should  be  inspected,  in  different  drops,  a  procedure 
involving  the  enumeration  of  about  1000  cells,  in  normal  blood. 
Except  in  high  leucocytoses,  the  number  of  leucocytes  is  usually 
estimated  indirectly,  by  determining  their  ratio  to  the  erythro- 
cytes, and  basing  their  actual  number  upon  this  figure.  This 
plan  (the  necessity  for  which  is  a  serious  drawback  to  the  use  of 
this  instrument)  is  followed  so  as  to  dispense  with  the  tedious 
filling  and  refilling  of  the  counting  chamber,  in  an  endeavor  to 
find  a  sufficient  number  of  leucocytes  to  serve  as  a  basis  for  the 
calculation,  should  the  latter  be  direct.  Ordinarily,  not  more 
than  two  of  these  cells  are  contained  in  an  area  including  20 
squares.  Gowers  1  claims  that  the  limit  of  error  with  his  instru- 
ment is  less  than  3  per  cent. 

After  use,  the  different  parts  of  the  instrument  are  to  be  thor- 
oughly cleaned  and  dried,  in  the  manner  already  described. 

For  making  rapid  numerical  estimates  of  the 
Oliver's  Hem-  erythrocytes  Oliver  has  designed  an  instrument 
ocytometer.  based  upon  the  following  principles:  When  a 
candle-flame  is  viewed  through  a  flat  glass  test- 
tube  filled  with  water,  a  bright  transverse  line  is  visible,  com- 
posed of  densely  packed,  minute  images  of  the  flame  produced 
by  the  longitudinal  corrugations  of  the  glass.  If  for  the  water  a 
mixture  of  blood  and  Hay  em's  solution2  is  substituted,  a  more  or 
less  opaque  fluid  results,  so  that,  in  low  dilutions,  this  illuminated 
line  is  invisible,  reappearing  only  when  a  definite  degree  of  higher 
dilution  is  reached,  by  the  gradual  addition  of  the  diluent ;  when 
this  point  has  been  obtained,  the  line  is  again  detected  as  a  bright, 
delicate  streak  horizontally  crossing  the  tube.  Experiments  having 
proved  that  the  development  of  such  a  line,  by  gradual  dilution 
of  the  blood  with  Hayem's  fluid,  is  an  accurate  gage  of  the  per- 
centage of  erythrocytes  in  the  specimen  tested,  it  remained  for 
Oliver  to  devise  a  hemocytometer  consisting  of  the  following 
essential  parts : 

1.  A  capillary  pipette  for  measuring  the  blood. 

2.  A  glass  dropper,  one  end  of  which  is  capped  by  a  rubber 
nipple,  the  other  by  a  short  rubber  nozle  which  fits  over  the  blunt 
end  of  the  pipette. 

3.  A  standard  graduated  tube,  in  which  the  blood  and  the 
diluent  are  mixed. 

1  Lancet,  1877,  vol.  ii,  p.  797.  2  For  formula  see  page  56. 


72       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


The  four  walls  of  the  tube  are  flattened  so  that  it  is  rectangular 
on  cross-section,  one  wall  being  provided  with  an  etched  scale 
indicating  units  from  10  to  120.  Each  of  these  divisions  is  equiv- 
alent to  50,000  erythrocytes,  the  point  marked  100  degrees  repre- 
senting the  arbitrary  normal  number,  5,000,000. 

Small-sized  wax  candles,  known  as  "Christmas  candles,"  are 
to  be  preferred  for  the  illumination,  as  they  give  the  small  flame 
requisite  to  obtain  a  sharply  defined  line,  but  the  flame  from  a 
gas-jet  turned  low  may  also  be  used  with  satisfaction. 

Method  0]  Use.—  In  making  the  observation  the  pipette,  which 
has  been  previously  cleaned  and  dried,  is  filled  with  blood  in  the 
usual  manner,  and  any  excess  of  blood  on  the  outside  carefully 

removed.  The  rubber 
nozle  of  the  dropper, 
filled   with  Hayem's 
fluid,  is  then  slipped 
over  the  blunt  end  of 
the  pipette,  and  the 
blood  washed  out  into 
the  graduated  tube  by 
squeezing  the  nipple. 
This  preliminary  dilu- 
tion is  continued  until 
the  column  in  the  tube 
rises  to  within  10  or  15 
degrees  below  the  fig- 
ure for  the  hemoglobin 
percentage  of  the  same 
blood,  this  having  been 
previously  determined. 
For  instance,  if  the 
hemoglobin  percentage  was  found  to  be  70,  the  diluting  fluid  is  added 
m  large  quantities  until  the  mixture  in  the  tube  reaches  to  about  the 
mark  60,  after  which  it  is  added  more  cautiously  and  in  smaller 
quantities  at  a  time,  careful  search  for  the  bright  line  being  made 
after  each  addition.    In  cases  of  chlorosis  and  of  pernicious  anemia, 
m  which  parallelism  between  the  hemoglobin  and  corpuscular  loss 
is  lacking,  it  is,  of  course,  impossible  to  depend  upon  the  hemo- 
globin percentage  as  an  index  to  the  amount  of  diluent  required, 
so  that  in  instances  of  this  kind  the  line  must  be  developed  more 
slowly,  by  making  a  smaller  primary  dilution  and  by  adding  the 
requisite  volume  of  liquid  more  deliberately. 

After  the  first  dropperful  of  diluent  has  been  added  to  the  con- 
tents of  the  tube,  the  latter  are  mixed  by  inverting  the  tube  a 


Fig.  23.— Method  of  Using  Oliver's  Hemocytometer. 
Showing  manner  in  which  the  blood  is  washed  from  the  capil- 
lary pipette  into  the  tube  containing  Hayem's  solution. 


COUNTING  THE  ERYTHROCYTES  AND  LEUCOCYTES. 


73 


number  of  times  with  the  thumb  held  over  its  mouth,  the  precau- 
tion being  taken  also  to  remove  the  thumb  by  drawing  it  over  the 
mouth  of  the  tube,  in  order  to  restore  to  its  contents  any  liquid 
which  may  have  adhered  to  the  skin.  The  tube  should  be  inverted 
thus  after  each  addition  of  the  diluting  fluid. 

The  steps  of  the  observation  succeeding  the  measuring  of  the 
blood  and  its  primary  dilution  are  to  be  made  in  a  dark  room, 
free  from  cross  lights,  the  candle  being  placed  about  ten  feet  dis- 
tant from  the  observer.  In  order  to  shut  out  the  diffused  light 
of  the  candle  the  tube  should  be  held  vertically  in  the  concavity 
formed  between  the  thumb  and  forefinger,  being  kept  close  to 
the  eye  while  searching  for  the  bright  line.  Oliver  states  that  the 
earliest  indications  of  this  line  are  obtained  by  turning  the  tube 
on  its  axis,  when  it  will  become  visible  at  the  sides. 

Apart  from  the  "personal  equation,"  the  serious  drawback 
to  this  test  is  its  failure  to  indicate  the  number  of  leucocytes, 
this  fact  alone  being  sufficient  to  curtail  its  use  for  routine  clinical 
work.  It  is  also  apparent  that  in  cases  of  marked  leucocytosis 
and  of  leukemia  the  optical  principles  of  the  test  must  necessarily 
fail  because  of  the  enormous  number  of  leucocytes  in  the  blood. 
Furthermore,  the  instrument  gives  false  results  with  blood  in 
which  conspicuous  deformities  of  the  erythrocytes  exist,  for  the 
reason  that  the  standard  tube  is  corrected  for  normally  shaped 
corpuscles,  so  that  blood  composed  largely  of  microcytes,  megalo- 
cytes,  or  poikilocytes  will  give  different  readings  from  blood  in 
which  the  cells  are  of  unaltered  biconcave  shape  and  of  normal 
size.  The  discrepancies  between  the  Oliver  and  the  Thoma- 
Zeiss  instruments  have  been  carefully  worked  out  by  Emerson 1 
i  and  by  Baumgarten.2 

This  method,  devised  by  Strong  and  Selig- 

Dry  Film     mann,3  aims  to  eliminate  errors  due  to  variations 

Method.  in  the  depth  of  the  Thoma-Zeiss  counting  chamber, 
and  at  the  same  time  to  furnish  permanent  speci- 
mens which  may  be  examined  at  any  subsequent  time.  It  is 
practically  a  simplification  of  the  method  suggested  by  Einhorn 
and  Laporte.4  The  principle  involved  consists  in  diluting  a 
measured  volume  of  fresh  blood  with  a  measured  volume  of  a 
diluent  with  which  a  suitable  differential  stain  is  combined,  a 
definite  quantity  of  the  mixture  then  being  spread  upon  a  glass 
slide,  allowed  to  evaporate,  mounted  in  the  ordinary  manner,  and 
examined  microscopically. 

1  Johns  Hopkins  Hosp.  Bull.,  1903,  vol.  xiv,  p.  9. 

2  Ibid.,  1902,  vol.  xiii,  p.  176. 

3  Brit.  Med.  Jour.,  1903,  vol.  ii,  p.  74.       4  Med.  News,  1902,  vol.  Ixxx,  p.  741. 


74       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

Two  different  diluting  fluids  are  used,  one  for  the  leucocytes 
and  one  for  the  erythrocytes.  Tabloids  (made  by  Parke,  Davis 
and  Company)  containing  0.25  gm.  of  sodium  chlorid  combined 
with  0.004  gm.  of  methyl- violet  (for  leucocytes)  and  with  0.0025 
gm.  of  eosin  (for  erythrocytes)  are  employed  for  making  the  dil- 
uents, instead  of  stock  solutions,  which  become  unstable  after  a 
short  time.  To  prepare  the  diluents  one  of  each  of  these  tabloids 
is  dissolved  in  30  c.c.  of  distilled  water  to  which  0.5  c.c.  of 
formalin  is  added,  the  mixture  then  being  filtered. 

Counting  the  Leucocytes. — Five  c.mm.  of  blood  are  sucked  up 
into  a  graduated  pipette,  and  then  blown  out  into  a  small  vessel 
containing  495  c.mm.  of  the  methyl-violet  diluent.  After  stirring, 
5  c.mm.  of  this  1:100  mixture  are  drawn  up  in  a  pipette  and 
deposited  upon  the  surface  of  a  glass  slide  so  as  to  form  a  film 
about  10  or  12  mm.  in  diameter.  The  film  thus  made  is  allowed 
to  evaporate  and  then  mounted  with  balsam  and  a  cover-glass. 

The  count  is  made  by  going  over  the  entire  area  of  the  film  with 
a  J-inch  dry  objective,  and  noting  the  number  of  violet-stained 
cells.  In  order  to  facilitate  this  procedure,  either  a  square  or  an 
oblong  ocular  diaphragm,  made  of  black  paper  or  of  metal, 
should  be  used,  together  with  a  mechanical  stage.  The  blood  dilu- 
tion being  1  :  100  and  the  volume  of  this  mixture  spread  upon 
the  slide  being  5  c.mm.,  the  number  of  leucocytes  per  c.mm. 
of  undiluted  blood  is  therefore  100  -:-  5,  or  20  times  the  total 
number  counted  in  the  entire  film.  For  example,  having  noted 
400  leucocytes  in  the  latter,  the  simple  formula  400  X  20  =  8000 
leucocytes  per  c.mm.,  gives  the  final  calculation.  An  error  of  50 
cells  in  the  count  alters  the  final  result  by  only  1000  cells — a  trivial 
matter. 

Counting  the  Erythrocytes. — In  this  instance  a  1 : 20,000  dilu- 
tion is  made,  by  mixing  5  c.mm.  of  the  above  1 : 100  blood  and 
methyl-violet  diluent  with  995  c.mm.  of  the  eosin  diluent.  After 
allowing  the  erythrocytes  to  stain  for  a  few  minutes,  5  c.mm.  of 
this  mixture  are  spread  over  a  slide,  as  described  above,  similarly 
mounted,  and  examined  microscopically,  the  erythrocytes  being 
recognized  by  their  rose-red  color.  The  number  of  erythrocytes 
per  c.mm.  of  undiluted  blood  is  4000  times  the  number  counted 
in  the  dry  eosined  film,  since  5  c.mm.  of  a  1 : 20,000  dilution  of 
the  blood  has  been  used;  thus,  20,000  -f-  5  =  4000.  For  instance, 
having  counted  1200  erythrocytes  in  the  5  c.mm.  film,  the  formula 
1200  X  4000  =  4,800,000  erythrocytes  per  c.mm.,  gives  the  final 
result. 

The  originators  of  the  dry  film  method  of  blood  counting 
insist  that  its  results  are  more  accurate  than  are  possible  with  a 


MICROSCOPICAL  EXAMINATION  OF  STAINED  SPECIMEN.  75 

hemocytometer.  In  three  Thoma-Zeiss  instruments,  three  years 
old,  they  found  figures  consistently  ten  per  cent,  higher  than  those 
obtained  by  new  instruments  of  the  same  design  and  make,  an 
error  which  could  be  explained  by  an  increase  of  o.oi  mm.  in 
the  depth  of  the  counting  chamber.  Counts  made  by  the  dry 
method  averaged  i.i  per  cent,  lower  than  those  in  which  the  hemo- 
cytometer was  used.  Several  sources  of  error,  however,  must  be 
guarded  against.  For  example,  in  making  the  dilutions,  unless 
every  trace  of  the  measured  5  c.mm.  of  whole  blood  is  blown 
from  the  pipette  into  the  diluting  fluid,  the  dilution  will  be  too 
high;  and  if,  in  making  the  film,  the  diluted  blood  is  blown  out 
too  forcibly,  the  film  will  be  scattered  and  ragged  and  stippled  with 
air-bubbles.  The  erythrocytes  may  stain  violet  instead  of  rose 
should  the  diluting  solution  not  be  perfectly  fresh.  The  leuco- 
cytes, which  may  stain  violet,  usually  take  the  color  of  eosin,  with 
the  eosin  dilution  for  erythrocytes.  Thus,  the  former  are  un- 
consciously counted  with  the  latter,  but  under  ordinary  circum- 
stances this  is  an  unimportant  error,  since  the  number  of  leuco- 
cytes is  comparatively  too  small  appreciably  to  affect  the  erythro- 
cyte count.  In  leukemia,  however,  the  error  may  be  suffi- 
ciently great  to  need  correction.  In  this  disease,  therefore,  all 
the  blood  cells,  red  and  white,  should  be  counted,  multiplied  by 
4000,  and  from  this  total  is  to  be  subtracted  the  total  leuco- 
cyte estimate  previously  determined,  the  result  being  obviously 
the  total  number  of  erythrocytes  per  c.mm.  Unfortunately, 
the  specimens  prepared  by  Strong  and  Seligmann's  technic  are 
marred  by  deposits  of  salt  crystals  and  by  masses  of  amorphous 
eosin,  both  at  the  edges  of  the  film  and  scattered  throughout  it. 
This  defect,  if  it  does  not  render  an  accurate  count  impossible, 
may  at  least  make  it  difficult  and  tedious.  In  a  passably  good 
specimen  the  counts  of  erythrocytes  and  leucocytes  together  should 
not  take  longer  than  half  an  hour. 

IV.  MICROSCOPICAL  EXAMINATION  OF  THE 
STAINED  SPECIMEN. 

The  microscopical  study  of  the  dried  and 
Objects  or    stained  blood  film,  which  should  supplement  the 
Staining.     methods  of  investigation  just  described,  is  for 
many  reasons  the  most  important  step  in  the 
clinical  examination  of  the  blood.    By  means  of  this  method 
of  " color  analysis"  it  is  possible  to  differentiate  easily  and  with 
absolute  certainty  the  various  forms  of  leucocytes,  and,  by  differ- 
ential counting,  to  calculate  the  relative  percentages  of  each 


76       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


variety  of  these  cells;  to  distinguish  the  several  structural  de- 
generative changes  affecting  chiefly  the  erythrocytes,  and  to  a 
less  extent  the  leucocytes;  and  to  recognize  and  classify  accord- 
ing to  their  histological  character  the  nucleated  forms  of  the  eryth- 
rocytes^ To^  sum  up,  in  the  words  of  Ehrlich,1  to  whom  we 
owe  this  rational  means  of  investigation :  "  Everything  that  is 
to  be  seen  in  the  fresh  specimens— apart  from  the  quite  unim- 
portant rouleaux  formation  and  ameboid  movements — can  be 
seen  equally  well,  and  indeed  much  better,  in  a  stained  prepara- 
tion; and  there  are  several  important  details  which  are  made 
visible  only  in  the  latter,  and  never  in  wet  preparations." 

According  to  the  classification  introduced 
TheAnilin  many  years  ago  by  Ehrlich,2  the  anilin  dyes 
Dyes.  are  divided  into  three  different  groups:  acid, 
basic,  and  neutral.  Acid  dyes,  or  compounds  in 
which  the  coloring  principle  acts  or  exists  as  an  acid,  possess  a 
special  affinity  for  cell  protoplasm,  and,  therefore,  are  generally 
employed  as  plasma  stains;  in  hematological  work  acid  fuchsin, 
eosin,  and  orange  G  are  the  principal  dyes  used  for  this  purpose! 
Basic  dyes,  or  compounds  in  which  the  coloring  principle  exists 
chemically  as  a  base  in  combination  with  a  colorless  acid,  are 
especially  useful  as  nuclear  stains,  since  they  exhibit  a  special 
affinity  for  chromatin  structures;  members  of  this  group  of 
dyes  commonly  used  in  blood  staining  are  methylene-blue,  tol- 
uidin-blue,  methyl-green,  methyl-violet,  thionin,  and  hema- 
toxylin. Neutral  dyes  are  the  coloring  principles  which  result 
from  the  mixture  of  solutions  of  an  acid  and  a  basic  dye;  they 
are  used  for  the  demonstration  of  the  so-called  neutrophile 
granules  of  the  leucocytes,  for  which  they  show  a  selective 
affinity. 

Cover- glass  Films. — For  the  preparation  of 
Preparing    the  dried  blood  films  it  is  advisable  to  have  at 
the  Films,    hand  at  least  half  a  dozen  perfectly  clean,  polished 
cover-glasses,  which  may  be  arranged  in  pairs 
on  a  sheet  of  white  paper  within  convenient  reach  of  the  examiner. 
After  having  wiped  away  the  blood  which  immediately  follows  the 
puncture,  a  minute  portion  of  the  next  drop  is  collected,  by  lightly 
touching  the  center  of  one  of  the  cover-glasses  to  its  summit,  care 
being  taken  to  avoid  bringing  the  polished  surface  of  the  glass  in 
contact  with  the  skin  of  the  patient's  finger.    The  charged  cover- 
glass  is  then  at  once  dropped,  blood  side  downward,  upon  the 

'Ehrlich  and  Lazarus,  "Die  Anaemie,"  Vienna,  1900  (Nothnaeel's  "Spec.  • 
Path.  u.  Therap.,"  vol.  viii,  No.  2).  '  ' 

2  Zeitschr.  f.  klin.  Med.,  1880.  vol.  i,  p.  555. 


MICROSCOPICAL  EXAMINATION  OF  STAINED  SPECIMEN.  77 


surface  of  the  second  glass  (Fig.  24),  with  the  result  that  the 
blood  quickly  spreads  out  in  a  thin  film  between  the  two,  and  ex- 
tends to  their  peripheries,  provided  that  the  proper  quantity  of 
blood  has  been  used  (Fig.  25).  As  soon  as  the  film  has  reached 
the  margins  of  both  cover-glasses,  they  are  rapidly  drawn  apart 
in  a  horizontal  direction,  so  that  the  surface  of  each,  when  thus 
separated,  is  covered  with  a  thin  layer  of  blood  (Fig.  26),  which 
should  be  rapidly  dried,  either  by  blowing  briskly  upon  its  sur- 
face or  by  holding  the  glass  for 
a  few  seconds  high  over  the 
flame  of  an  alcohol  lamp.  If 
care  is  taken  to  use  but  a  very 
small  drop  of  blood,  to  avoid 
pressure  in  opposing  the  sur- 
faces of  the  two  cover-glasses, 
and  to  separate  them  in  their 
true  horizontal  planes,  the 
films  will  consist  of  a  single    FlG-  24-~ superimposing  the  charged  cover- 

1  °  GLASS. 

layer  01  corpuscles,  most  of 

which  will  be  sufficiently  isolated  to  allow  the  study  of  their 
individual  morphology  and  other  characteristics.  The  beginner 
should  persistently  practise  the  technic  of  film-making  until  he 
is  able  to  obtain  a  satisfactory  percentage  of  good  specimens  from 
every  batch  of  spreads.  Thick,  uneven  spreads,  in  which  the 
corpuscles  are  heaped  up  and  glued  together  in  dense  masses, 

are  of  no  value  for  histologi- 
cal study  of  the  cells,  al- 
though they  are  often  useful 
when  searching  for  parasites 
in  blood  containing  very 
few  organisms.  In  such 
instances  Ross1  advises 
smearing  the  blood  thickly 
on  the  slide,  and,  after  it 

Fig.  25-— Drawing  Apart  the  Cover-glasses.  naS  dried,^  Washing  OUt  the 

hemoglobin  with  water. 
The  film  thus  dehemoglobinized,  unfixed,  and  still  wet,  is  then 
stained  with  aqueous  solutions  of  eosin  and  methylene-blue,  washed 
with  water,  and  mounted.  The  parasites  stain  the  color  of  the  basic 
dye,  but  the  erythrocytes,  since  they  contain  no  hemoglobin,  are 
practically  colorless.  This  method,  while,  of  course,  unsuitable  for 
differential  counting,  may  be  of  value  in  certain  cases  of  malarial 
fever,  filariasis,  and  trypanosomiasis. 

1  Thompson  Yates  and  Johnston,  Lab.  Rep.,  1903,  vol.  v,  p.  117. 


78       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


The  films,  after  having  been  dried,  may  be  placed  in  a  pill  box 
and  labeled,  to  await  fixation  and  staining  at  the  examiner's  con- 
venience. Dried  specimens  will  keep  for  an  indefinite  period  if 
not  exposed  to  dust  or  to  moisture.    Unfixed  cover-glass  specimens 

of  leukemic  blood  have 
been  "  triple-stained  "  by 
the  writer,  with  perfect 
results,  more  than  three 
years  after  they  were 
spread.  With  the  Rom- 
anowsky  method,  how- 
ever, the  fresher  the 
specimen,  the  sharper  the 
stained  film. 

Many  histologists  recommend  the  use  of  special  forceps  for 
holding  the  cover-glasses  while  making  the  spreads,  claiming  thus 
to  avoid  the  injurious  effects  upon  the  blood  corpuscles  which  may 
be  caused  by  the  moisture  of  the  fingers  if  they  come  in  con- 


Fig.  26. — The  Cover-glasses  after  Separation. 


Fig.  27. — -Spreading  a  Film  with  Two  Glass  Slides. 


tact  with  the  films.    The  careful  worker  need  have  no  fear  on  this 
score,  for  if  the  covers  are  held  in  the  manner  shown  in  the  illus- 
trations, this  accident  will  not  occur.    A  pair  of  light  thumb 
forceps  is  useful  for  picking  up  the  cover-glasses 
from  a  flat  surface,  but  the  employment  of  spe- 
cial spreading  forceps  is  quite  unnecessary. 

Glass  Slide  Films. — Some  prefer  to  make  the 
spread  upon  an  ordinary  glass  slide,  but  this 
method  rarely  yields  as  thin  and  even  a  film 
as  the  one  just  described,  though  it  is  easier 
to  learn.  A  small-sized  drop  of  blood  is  dis- 
tributed along  the  edge  of  a  glass  slide,1  which  is  then  held 
at  an  angle  of  45  degrees  against  the  surface  of  another  slide, 

1  Waldstein's  smearing  slip  (Med.  Rec.,  1896,  vol.  1,  p.  385),  made  of  crown 
glass,  with  its  "  spreading  edge  "  ground  smooth  and  round,  answers  much  better 
than  an  ordinary  slide. 


Fig.  28. — Spreading  a 
Film  with  Cigar- 
ette Paper. 


MICROSCOPICAL  EXAMINATION  OF  STAINED  SPECIMEN.  79 

over  which  it  is  rapidly  drawn,  with  moderate  pressure,  thus 
depositing  a  thin  film  of  blood  upon  the  surface  of  the  latter 
(Fig.  27).  Instead  of  a  glass  slide,  a  leaf  of  cigarette  paper 
or  a  slip  of  thin  tissue-paper,  trimmed  to  a  narrower  width 
than  that  of  the  slide,  may  be  used  as  a  spreader  (Fig.  28).  A 
fair  spread  may  also  be  made  by  depositing  a  drop  of  blood  upon 
a  slide,  near  one  end,  and  then  distributing  it  by  means  of  a  needle 
or  a  glass  rod,  the  shaft  of  which  is  applied  to  the  drop  with  even 
pressure.  The  film  thus  made  is 
immediately  dried  in  air  and  treated 
as  a  cover-glass  spread. 

As  a  step  pre- 

Fixation      liminary  to  stain- 

Methods.  ing,  the  albuminoid 
principles  of  the 
blood  must  be  fixed,  by  exposing 
the  dried  film  either  to  a  high  de- 
gree of  dry  heat  or  to  various  chemi- 
cal hardening  agents,  the  choice  be- 
tween these  two  methods  being  de- 
termined by  the  character  of  the 
staining  solution  to  be  used  subse- 
quently. 

Heat  Fixation. — This  method 
may  be  employed  with  any  of  the 
stains  described  in  the  following    Fic.29.-oven  for  Fixing  blood  films. 
pages,  except  with  Wright's  solu- 
tion ;  it  must  be  used  with  Ehrlich's  triple  stain,  in  preference  to 
fixation  by  chemicals,  in  order  to  obtain  crisp,  clean-cut  pictures. 

The  author  is  accustomed  to  use  an  oven,  such  as  is  illustrated 
above  (Fig.  29),  consisting  of  a  copper  box  with  a  heavy  bottom 
and  hinged  cover,  mounted  on  an  ordinary  iron  burette  stand,  by 
means  of  a  thumb-screw.  A  small  "baby"  Bunsen  lamp  placed 
underneath  the  box  furnishes  the  requisite  degree  of  heat,  the 
temperature  being  indicated  by  a  thermometer  mounted  at  one  end 
and  resting  upon  the  floor  of  the  oven.  By  sliding  the  latter  up  and 
down  the  vertical  rod  to  which  it  is  attached  the  desired  degree  of 
temperature  may  be  obtained  at  will.  The  blood  films  are  inclosed 
in  the  copper  box,  and  the  latter  fixed  at  a  point  eight  inches  above 
the  summit  of  the  burner,  after  which  the  gas  is  lighted  and  allowed 
to  burn  until  the  temperature,  as  indicated  by  the  thermometer,  has 
gradually  crept  up  to  1600  C.  As  soon  as  this  degree  of  heat  has 
been  reached  the  gas  is  extinguished,  the  cover  of  the  oven  thrown 
back,  and,  after  the  temperature  has  fallen  to  300  C,  the  films 


EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


removed,  being  now  thoroughly  fixed  and  ready  for  staining. 
Fifteen  minutes  suffice  for  the  whole  operation,  from  the  time  the 
gas  is  lighted  until  the  films  have  been  removed  and  cooled  for 
staining. 

A  less  satisfactory  method  of  heat  fixation  is  by  the  use  of  a 
copper  plate  upon  which  the  films  are  kept  at  a  temperature  of 
from  ioo°  to  no°  C.  for  from  one-half  to  one  hour.    The  ap- 
paratus used  for  this  purpose  consists  of  a  rectangular  plate  of 
sheet  copper,  about  fifteen  inches  long  by  four  inches  wide  by 
one-sixth  of  an  inch  thick.    An  alcohol  or  a  Bunsen  lamp  burns 
under  one  end  of  the  plate,  which  is  elevated  about  six  inches 
above  the  flame  by  four  metal  legs.    After  having  heated  the 
plate  for  ten  or  fifteen  minutes,  until  a  relatively  constant  tem- 
perature becomes  established,  water  is  dropped  upon  its  surface 
beginning  with  the  end  farthest  from  the  flame,  until  a  point  is 
reached  at  which  the  water  boils.    This  part  of  the  plate  is  con- 
sidered to  have  a  temperature  of  ioo°  C,  and  at  this  point  the 
blood  films  are  placed,  "spread"  side  downward,  and  heated  for 
the  required  time.    No  one  with  much  blood  staining  to  do  will 
choose  this  method  of  prolonged  heating  at  a  relatively  low,  ap- 
proximate temperature  in  preference  to  brief  heating  at  a  high, 
definite  temperature  in  an  oven.    The  use  of  the  latter,  aside 
from  its  convenience  as  a  time-saver,  insures  constant  and  cer- 
tain results,  for  overheating  and  underheating  of  the  blood  film  may 
be  avoided,  since  the  degree  of  heat  is  exactly  indicated  and  easily 
controllable.    In  triple-stained  specimens  the  blood  cells  are  much 
more  brilliantly  colored  and  sharply  differentiated  when  the  films 
are  fixed  at  a  temperature  of  1600  C.  than  at  a  lower  degree. 

Should  nothing  but  a  Bunsen  or  an  alcohol  lamp  be  available, 
the  cover-glass  film,  held  with  a  pair  of  forceps,  may  be  fixed  by 
passing  it  rapidly  through  the  flame  thirty  or  forty  times  and  then 
holding  it  twelve  or  fifteen  inches  above  the  flame  for  a  minute 
°.r  S0,  .  This  makeshift  method,  which  is  often  sufficient  for  a  hur- 
ried clinical  examination,  usually  gives  fair,  and  sometimes  very 
good,  results,  but  the  fixation  is  generally  uneven,  and  the  speci- 
men is  frequently  scorched  in  some  places  and  underfixed  in 
others. 

Chemical  Fixation.—  Immersion  of  the  dried  films  in  ether,  in 
absolute  alcohol,  or  in  a  mixture  of  equal  parts  of  the  two  (Niki- 
foroff's  method)  gives  satisfactory  results  with  specimens  stained 
by  any  of  the  single  basic  dyes,  or  with  the  simpler  double  stains, 
such  as  eosin  and  methylene-blue  or  hematoxylin.  The  time  of 
fixation  varies  from  five  to  fifteen  minutes  with  any  of  these  agents, 
the  specimen  then  being  dried  without  using  heat  and  stained 


MICROSCOPICAL  EXAMINATION  OF  STAINED  SPECIMEN.       8 1 

without  previously  washing.  If  time  is  an  object,  the  specimens 
may  be  boiled  for  one  minute  in  a  test-tube  containing  absolute 
alcohol,  as  advised  by  Ehrlich.1  Some  workers  employ  one 
minute's  fixation  by  a  one  per  cent,  alcoholic  solution  of  forma- 
lin (Benario's  method),  while  others  prefer  to  expose  the  films  to 
the  vapors  of  this  chemical  for  the  same  length  of  time.  Five 
to  ten  minutes'  immersion  in  a  concentrated  aqueous  solution  of 
mercuric  chlorid  is  one  of  the  older,  but  useful,  methods  of  fixation. 
Solley 2  has  recently  suggested  that  the  film  be  flooded  with  a  two  per 
cent,  aqueous  solution  of  chromic  acid,  which  is  washed  off  after 
exactly  thirty  seconds,  the  specimen  being  then  stained  while  still 
wet ;  he  recommends  this  procedure  as  a  substitute  for  heat  in  fixing 
specimens  for  triple  staining,  but  the  method,  while  fairly  good, 
cannot  be  regarded  as  entirely  satisfactory.  In  the  author's  hands 
both  Merck's  methyl  alcohol  (five  minutes)  and  a  two  per  cent, 
aqueous  solution  of  osmic  acid  (half  a  minute)  have  been  found  to 
be  fair  substitutes  for  heat  fixation. 

In  hematological  as  in  other  histological  work 
Methods  of  the  choice  of  a  staining  method  is  determined  by 

Staining     the  character  of  the  investigation  to  be  undertaken. 

For  general  clinical  purposes  it  is  advantageous 
habitually  to  employ  some  routine  method  by  means  of  which 
the  greatest  possible  number  of  elements  may  be  demonstrated 
in  a  single  blood  film,  this  procedure  being  known  as  panoptic 
staining.  Thus,  by  using  a  solution  containing  several  of  the 
anilin  dyes,  the  stroma  of  the  erythrocytes,  the  cell  granules,  the 
cell  nuclei,  and  the  various  blood  parasites  may  be  simultaneously 
stained  each  in  a  characteristic  manner,  owing  to  the  selective 
affinity  displayed  by  the  different  coloring  principles  of  the  mix- 
ture toward  these  several  histological  elements.  The  most  useful 
solutions  which  have  been  devised  for  this  purpose  are  Wright's 
alkaline  eosinate  of  methylene-blue 3  and  Ehrlich's  triacid  mixture.4 
Practically  all  the  information  that  it  is  possible  to  derive  from 
the  study  of  the  stained  dry  blood  film  may  be  obtained  with  the 
aid  of  these  two  solutions. 

Simple  combinations  of  an  acid  and  a  basic  dye,  such  as  eosin 
and  methylene-blue,  eosin  and  hematoxylin,  and  orange  and  hema- 
toxylin, are  used  by  many  investigators,  chiefly  for  the  purpose 
of  staining  the  cell  stroma  and  the  nuclear  structures;  but,  as  a 
general  rule,  such  mixtures  are  not  adapted  for  clinical  work, 

1  Loc.  cit. 

2  Med.  and  Surg.  Reports  of  the  Presbyterian  Hospital,  New  York,  1900,  vol. 
iv,  p.  169. 

3  Jour.  Med.  Research,  1902,  vol.  vii,  p.  138.  4  Loc.  cit. 

6 


82       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

since  with  none  of  them  is  it  possible  to  differentiate  the  neutro- 
phile  granules.  Solutions  of  a  single  dye  are  but  seldom  used 
except  for  the  demonstration  of  special  elements,  such,  for  in- 
stance, as  the  staining  of  the  malarial  parasite  by  thionin,  the 
mast  cells  by  dahlia,  and  certain  bacteria  by  the  basic  dyes,  such 
as  methylene-blue  and  gentian-violet.  Since  by  this  method  of 
staining  only  the  particular  elements  toward  which  the  dye  reacts 
are  differentiated,  the  employment  of  single  stains  is  inadequate 
for  the  study  of  the  general  morphology  of  the  blood  cells. 

The  following  formulas  will  be  found  sufficient  for  all  purposes 
of  clinical  investigation: 

Wright's  Stain.— This  excellent  stain  is  an  improvement  on 
Irishman's  modification1  of  the  late  Louis  Jenner's  solution,2  and 
is  so  prepared  that  its  basic  constituent  (methylene-blue)  acquires 
the  polychromatic  properties  of  the  Romanowsky  stain,3  so  valuable 
in  differentiating  chromatin  and  cytoplasm.  Wright's  stain  gives 
sharp  pictures  of  cell  protoplasm,  chromatin,  and  nuclei,  and  is 
especially  useful  in  studying  the  lymphocytes,  the  mast  cells,  the 
blood  plaques,  and  the  finer  structure  of  the  malarial  parasite. 
It  is  prepared  according  to  the  following  somewhat  complicated 
formula : 

1.  To  a  0.5  per  cent,  aqueous  solution  of  sodium  bicarbonate 
contained  in  an  Erlenmeyer  flask  add  one  per  cent,  of  Griibler's 
methylene-blue  (" medicinal"),  and  steam  the  mixture  in  a 
sterilizer  for  one  hour,  counting  from  the  time  " steam  is  up."4 
This  step  not  only  serves  to  develop  the  polychromatic  property  of 
the  alkaline  methylene-blue,  but  increases  its  power  as  a  nuclear 
and  granular  stain. 

2.  Cool  the  bicarbonized  methylene-blue  solution  after  steam- 
ing, and  then,  without  filtering,  add  to  it,  meanwhile  stirring  with  a 
glass  rod,  sufficient  of  a  1:1000  aqueous  solution  of  Griibler's 
yellowish  eosin  ("water  soluble")  to  change  the  color  of  the 
solution  from  blue  to  purple,  with  a  surface  scum  of  a  yellowish, 
metallic  luster.  About  500  c.c.  of  the  methylene-blue  solution  to 
100  c.c.  of  the  eosin  solution  are  required  to  produce  this  change. 

J  Brit-  Med.  Jour.,  1901,  vol.  ii,  p.  757.  2  Lancet,  1899,  vol.  i,  p.  370. 

3  Centralbl.  f.  Bakt,  1899,  vol.  xxv,  p.  764. 

4  When  a  steam  sterilizer  is  not  available,  polychrome  blue  may  be  developed 
by  heating  the  methylene-blue  solution  with  freshly  precipitated  silver  oxid.  Dan- 
iels ("Studies  in  Laboratory  Work,"  London,  1903,  p.  63)  directs  that  a  solution 
of  sodium  hydrate  be  added  to  one  of  silver  nitrate  until  no  more  precipitate  forms, 
the  precipitate,  silver  oxid,  being  then  washed  until  the  washings  are  neutral  to 
litmus-paper.  This  neutral  precipitate  is  added  to  the  methylene-blue  solution 
and  allowed  to  stand  for  twenty-four  hours,  when  the  supernatant  fluid  is  decanted 
off  from  the  sediment  and  filtered  before  using.  Polychrome  blue  thus  prepared 
is  treated  according  to  the  above  directions  for  making  Wright's  solution. 


MICROSCOPICAL  EXAMINATION  OF  STAINED  SPECIMEN. 


3.  Collect,  by  filtration,  this  scum  (which  consists  of  a  granular 
black  precipitate),  and  dry,  without  washing.  When  dry,  make 
of  it  a  saturated  solution  in  methyl  alcohol.  Three-tenths  of  a 
gram  of  the  dry  precipitate  saturates  100  c.c.  of  methyl  alcohol. 

4.  Filter  the  alcoholic  solution  of  the  precipitate  and  add  to  the 
filtrate  25  per  cent,  of  methyl  alcohol.  For  80  c.c.  of  the  filtrate,  the 
amount  usually  available,  20  c.c.  of  methyl  alcohol  are  required. 
This  alcoholic  solution  is  used  for  staining.  It  does  not  deteriorate 
with  age  if  kept  in  a  well-corked  bottle,  and  is  sufficiently  dilute 
to  prevent  precipitation  during  staining,  an  accident  which  was 
the  chief  drawback  to  Jenner's  original  stain. 

Technic  of  Staining. — Owing  to  the  methyl  alcohol  which  it 
contains,  Wright's  solution  fixes  and  stains  the  blood  film  simul- 
taneously, so  that  preliminary  fixation  may  be  omitted. 

The  unfixed  film  is  stained  for  one  minute,  as  much  of  the 
solution  being  used  as  the  cover-glass  will  hold  without  spilling. 
Next,  to  the  staining  fluid  upon  the  specimen  are  added,  drop  by 
drop,  eight  or  ten  drops  of  distilled  water — sufficient  to  develop 
a  reddish  tint  at  the  margins  of  the  cover-glass  and  a  semitrans- 
lucency  in  the  stain,  with  a  metallic  scum  on  the  surface.  The 
stain,  thus  diluted,  is  allowed  to  act  for  two  or  three  minutes,  when 
it  is  rinsed  off  with  water,  showing  that  the  film  has  become 
stained  deep  blue  or  purplish.  The  final  step  in  the  process  is  the 
decolorization  of  the  overstained  specimen  and  the  differentiation 
of  its  histological  elements.  This  is  accomplished  by  washing 
with  water  until  the  color  of  the  film  changes  to  yellowish  or  pink. 
From  one  to  three  minutes'  washing,  depending  upon  the  intensity 
of  the  staining,  is  required  to  reach  the  desired  tint.  The  specimen 
is  then  dried  between  filter-paper  (never  by  heat),  and  mounted 
in  balsam. 

Wright's  stain  gives  the  following  results :  erythrocytes,  orange 
or  pink;  nuclei  of  the  leucocytes,  blue  or  dark  lilac;  neutrophile 
granules,  lilac;  eosinophile  granules,  pink;  fine  basophile  granules, 
deep  blue;  and  coarse,  mast  cell  granules,  deep  royal  purple. 
The  nuclei  of  the  erythroblasts  and  bacteria  stain  various  shades 
of  blue,  and  the  blood  plaques  purplish,  flecked  with  red. 

The  body  of  the  malarial  parasite  stains  blue,  and  its  chromatin 
varies  from  lilac  to  red  to  almost  black. 

Aside  from  its  obvious  value  as  a  panoptic  staining  fluid,  this 
solution  will  often  prove  of  great  convenience  for  the  reason  that 
it  does  not  require  special  fixation  of  the  blood  film. 

Ehrlich's  Triacid  Stain.— This  "  triple  stain,"  containing 
one  basic  and  two  acid  dyes  (methyl-green,  orange  G,  and  acid 
fuchsin),  is  peculiar  in  that  a  chemical  combination  is  formed  by 


84       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


its  acid  and  basic  components,  which  may  be  regarded  as  a  neutral 
coloring  principle,  serving  the  purpose  of  selectively  staining  the 
so-called  neutrophile  elements  for  which  the  primary  components 
of  the  mixture  have  no  affinity.  With  this  stain  histological 
structures  having  an  affinity  for  the  acid  dyes  are  stained  the  color 
of  one  of  its  acid  constituents,  basic  structures  the  color  of  its 
basic  dye,  and  structures  having  an  equal  affinity  for  acid  and 
basic  dyes  the  color  of  the  neutral  compound^/ 

Saturated  aqueous  solutions  of  the  three  dyes  are  first  pre- 
pared, and  allowed  to  stand  for  several  days  until  they  have  be- 
come thoroughly  cleared.  It  is  essential  that  the  anilin  dyes  used 
for  making  these  "stock"  solutions  should  be  chemically  pure,  to 
insure  which  the  products  of  Griibler  or  of  the  Berlin  Anilin  Dye 
Company  should  invariably  be  chosen.  From  these  saturated 
solutions  the  following  mixture  is  made: 

Acid  fuchsin  solution   6-7  c.c. 

Orange  G  solution  ..13-14  c.c. 

Distilled  water  15  c.c. 

Absolute  alcohol  15  c.c. 

Mix  the  above  thoroughly  and  add,  drop  by  drop,  with  con- 
tinuous agitation,  in  the  following  order : 

Methyl -green  solution   12.5  c.c. 

Absolute  alcohol   10.0  c.c. 

Glycerin   10.0  c.c. 

The  mixture  should  under  no  circumstance  be  filtered,  but 
allowed  to  stand  for  about  twenty-four  hours  in  order  that  a  slight 
precipitate  may  form.  As  soon  as  this  occurs  the  stain  is  ready 
for  use,  the  necessary  quantity  being  pipetted  from  the  super- 
natant fluid  without  disturbing  the  precipitate. 

Technic  of  Staining. — The  heat-fixed  film,  held  preferably 
with  a  pair  of  Stewart's  staining  forceps,  is  flooded  with  the  stain, 
which  is  washed  off  in  running  water  after  the  lapse  of  from  five 
to  eight  minutes,  the  specimen  then  being  dried  by  gentle  heat 
and  mounted  in  xylol  balsam  or  in  cedar  oil. 

In  the  specimen  thus  prepared  the  stroma  of  the  erythrocytes  is 
stained  orange,  the  nuclei  of  the  leucocytes  greenish-blue,  the  neu- 
trophile granules  violet  or  lavender,  and  the  eosinophile  granules 
copper  red.  The  nuclei  of  the  erythroblasts  react  with  varying 
degrees  of  intensity  toward  the  basic  component  of  the  mixture, 
those  of  the  normoblasts  staining  deep  purple  or  black,  and  those 
of  the  megaloblasts  pale  green  or  greenish-blue.  The  basophile 
granules  remain  unstained,  appearing  as  dull  white,  coarse, 
stippled  areas  in  the  cell  protoplasm — "negative  staining."  In 
order  to  stain  these  granules,  as  well  as  the  basic  protoplasm  of 


MICROSCOPICAL  EXAMINATION  OF  STAINED  SPECIMEN.  85 


the  lymphocytes,  Hewes 1  suggests  that  the  triple-stained  film, 
after  having  been  washed,  be  subjected  for  from  one-half  second 
to  ten  seconds  to  Loffler's 2  methylene-blue  solution,  after  which  it 
is  again  washed,  and  mounted  as  above  directed.  This  modifica- 
tion is  of  undoubted  value,  chiefly  because  it  usually  enables  one 
to  differentiate  the  larger  forms  of  lymphocytes  from  the  large 
mononuclear  leucocytes.  Malarial  and  other  parasites  are  also 
distinctly  stained  by  this  method. 

Unsatisfactory  results  with  the  triple  stain,  provided  that  the 
latter  is  properly  made,  can  almost  always  be  attributed  to  faulty 
fixation.  As  already  remarked,  heat  is  the  only  method  of  fixa- 
tion which  will  insure  faultless  differentiation  in  the  specimen 
stained  with  this  mixture.  The  perfect  specimen  is  of  a  deep, 
rich  orange  tint  to  the  naked  eye;  if  underheated,  the  film  reacts 
too  strongly  toward  the  acid  fuchsin  of  the  mixture,  and,  conse- 
quently, is  the  color  of  this  dye;  if  overheated,  the  plasma  stain, 
orange  G,  is  but  feebly  displayed,  so  that  the  color  of  the  film  is 
pale  lemon  yellow.3  As  a  stain  for  general  clinical  work  Ehrlich's 
is  inferior  to  Wright's.  Although  a  sharper  neutrophile  stain,  it 
reacts  feebly  toward  basophile  structures,  and  requires  careful 
and  skilful  heat  fixation  of  the  films. 

Prince's  Stain. — This  mixture,  which  consists  of  an  aqueous 
solution  of  one  basic  and  two  acid  dyes,  is  an  excellent  stain  for 
the  differentiation  of  both  nuclei  and  granules,  and  may  be  em- 
ployed as  a  fair  substitute  for  either  of  the  two  preceding  solutions. 
It  should  be  made  in  this  manner: 

Saturated  aqueous  solution  of  toluidin  blue  24  c.c. 

Saturated  aqueous  solution  of  acid  fuchsin   1  c.c. 

Two  per  cent,  aqueous  solution  of  eosin   2  c.c. 

These  solutions  are  mixed  in  the  order  named,  and  shaken 
briskly  for  several  minutes,  so  as  to  secure  complete  precipitation 
of  the  basic  toluidin  blue  by  the  acid  dyes.  The  solution,  which 
should  not  be  filtered,  is  ready  for  use  as  soon  as  made.  Only 
the  supernatant  fluid  should  be  employed,  care  being  taken  not 
to  disturb  the  sediment. 

Technic  oj  Staining. — If  a  newly  made  solution  is  used,  the 
films  are  stained  for  from  one-half  to  one  minute,  after  which  they 
are  rinsed  in  water,  dried  in  air,  and  mounted ;  but  if  the  solution 
has  stood  for  several  weeks,  its  basic  constituent  becomes  less 

1  Boston  Med.  and  Surg.  Jour.,  1899,  vol.  cxli,  p.  39. 

2  Saturated  alcoholic  solution  of  methylene-blue,  30  c.c;  1  :  10,000  aqueous 
solution  of  potassium  hydrate,  100  c.c. 

3  A  reliable  triacid  stain,  made  according  to  Ehrlich's  formula,  is  sold  by 
Messrs.  Shinn  and  Kirk,  Philadelphia. 


86       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


active,  so  that  the  specimen  requires  to  be  stained  for  from  five  to 
ten  minutes.  Either  chemical  or  heat  fixation  of  the  blood  film 
may  be  used  with  this  stain,  both  methods  giving  equally  sharp  dif- 
ferentiation. Prince's  solution  colors  the  erythrocytes  rose-red,  the 
nuclei  of  the  leucocytes  and  erythroblasts  blue,  the  neutrophile 
granules  pink,  the  eosinophile  granules  maroon,  and  the  fine  and 
coarse  basophile  granules  blue.  Blood  parasites  are  also  stained 
the  color  of  the  basic  dye. 

Double  Staining  with  Eosin  and  Methylene-blue.— 
Crisp,  clear  pictures  of  nuclear  and  stroma  structures,  of  the  ma- 
larial parasites,  and  of  the  basophile  granules  may  be  obtained 
by  the  use  of  these  two  dyes,  and  to  investigations  of  this  nature 
should  this  staining  method  be  restricted.  It  is  impossible,  for 
example,  accurately  to  distinguish  a  large  lymphocyte  from  a 
myelocyte  in  a  specimen  stained  in  this  manner,  so  that  for  differ- 
ential counting  a  more  elaborate  stain  is  essential.  In  films  stained 
by  this  method  the  stroma  of  the  erythrocytes  and  the  eosinophile 
granules  react  toward  the  acid  dye,  staining  the  color  of  eosin; 
while  the  nuclei  of  the  leucocytes  and  erythrocytes,  the  basophile 
granules,  and  all  blood  parasites  show  an  affinity  for  the  basic 
dye,  being  colored  various  shades  of  blue.  The  protoplasm  of 
the  polynuclear  neutrophiles  is  either  colorless  or  tinged  a  deli- 
cate pink,  the  granules  of  these  cells  remaining  unstained. 

The  author  has  always  found  the  following  simple  formula  de- 
pendable: 

Eosin  (aqueous),  to  which  sufficient  water  has  been  added 

for  solution   o  <?  em 

Absolute  alcohol   0  ^  ^.c. 

Saturated  aqueous  solution  of  methylene-blue  96.0  cx! 

.  Technic  of  Staining. —Films  are  fixed  by  immersion  for  ten 
minutes  in  absolute  alcohol  or  in  equal  parts  of  absolute  alcohol 
and  ether.  The  cover-glass  is  flooded  with  the  stain,  gently 
heated  for  one  minute  over  a  Bunsen  flame,  allowed. to  stain 
without  heat  for  two  or  three  minutes  longer,  and  then  thoroughly 
washed  in  running  water,  dried  in  air,  and  mounted. 

Another  method  of  staining  with  eosin  and  methylene-blue, 
slower  than  the  above,  but  as  a  rule  giving  sharper  differentiation, 
is  to  stain  without  heat  for  five  minutes  with  a  0.5  per  cent,  solu- 
tion of  eosin  in  absolute  alcohol  to  which  an  equal  quantity  of 
water  is  added.  Then,  after  having  washed  off  the  eosin  solution 
and  dried  the  film  in  air,  the  specimen  is  counterstained  for  one 
minute  or  less  with  a  saturated  aqueous  solution  of  methylene- 
blue,  after  which  it  is  rinsed  again  in  water,  dried  in  air,  and 
mounted. 


MICROSCOPICAL  EXAMINATION  OF  STAINED  SPECIMEN.  87 


Among  the  many  other  methods  of  staining  with  eosin  and 
methylene-blue  those  suggested  by  Chenzinsky,1  by  Plehn,2  by 
Holmes,3  by  Laporte,4  and  by  Hastings5  will  be  found  the  most 
useful. 

Double  Staining  with  Eosin  and  Hematoxylin. — By  the 
employment  of  these  two  dyes  the  erythrocytes  and  the  eosinophile 
granules  are  stained  the  color  of  eosin,  and  all  nuclei  and  parasites, 
the  color  of  hematoxylin.  This  method,  which  is  decidedly  in- 
ferior to  staining  with  the  eosin  and  methylene-blue  mixtures  just 
described,  is  useful  for  little  else  than  the  study  of  nuclear  struc- 
tures. It  should  not  be  used  for  differential  counting,  since  in 
films  stained  in  this  manner  the  neutrophile  granules  are  invisible. 
Ehrlich6  recommends  this  formula: 


Eosin  (cryst.)   0.5  gm. 

Hematoxylin   2.0  gm. 

Absolute  alcohol  100.0  c.c. 

Distilled  water  100.0  c.c. 

Glycerin  100.0  c.c. 

Glacial  acetic  acid   10.0  c.c. 

Alum  in  excess. 


This  mixture  must  "age"  for  several  weeks  before  it  can  be  used  for  staining. 

Technic  oj  Staining. — Specimens,  fixed  either  chemically  or 
by  heat,  are  stained  for  from  one-half  hour  to  two  hours,  thor- 
oughly washed  in  water,  dried,  and  mounted.  In  order  to  obtain 
the  best  results,  it  is  advisable  to  filter  the  solution  before  using, 
and  to  wash  the  films  very  thoroughly  after  staining. 

If  time  is  an  object,  the  following  rapid  method  may  be  substi- 
tuted for  the  above :  The  film  is  first  stained  for  about  five  minutes 
with  a  0.5  per  cent,  solution  of  aqueous  eosin  in  50  per  cent, 
alcohol,  washed,  and  dried  in  air;  it  is  then  counterstained  for 
about  one-half  minute  with  Delafield's  hematoxylin,7  washed 
a  second  time,  and  mounted  in  the  usual  manner. 

Staining  with  Thionin. — Thionin  (also  known  as  the  "violet 
of  Hoyer"  and  the  "violet  of  Lauth")  is  an  excellent  stain  for 

1  Zeitschr.  f.  wiss.  Mik.,  1894,  vol.  xi,  p.  260. 

2  "  Aetiologische  undklinische  Malaria  Studien,"  Berlin,  1890. 

3  Jour.  Amer.  Med.  Assoc.,  1898,  vol.  xxx,  p.  303. 

4  Med.  Rec,  1903,  vol.  lxiii,  p.  1017. 

5  Johns  Hopkins  Hosp.  Bull.,  1904,  vol.  xv,  p.  122.  6  Loc.  cit. 

7  This  solution  is  made  by  first  adding  4  gm.  of  hematoxylin  crystals,  dis- 
solved in  25  c.c.  of  alcohol,  to  400  c.c.  of  a  saturated  aqueous  solution  of  ammonia- 
alum.  The  mixture  is  left  exposed  to  the  sunlight  and  air  in  an  uncorked  bottle 
for  four  days,  at  the  end  of  which  time  it  is  filtered,  and  mixed  with  100  c.c.  each 
of  methyl  alcohol  and  glycerin.  This  solution  is  allowed  to  stand  until  it  becomes 
dark  colored,  when  it  is  filtered  and  placed  in  a  tightly  corked  bottle  to  "age" 
for  at  least  two  months  before  it  can  be  used  successfully  for  staining.  Owing  to 
the  complicated  manner  in  which  Delafield's  hematoxylin  must  be  prepared,  it  is 
usually  preferable  to  purchase  it  ready-made,  from  a  dealer  in  microscopical  sup- 
plies, Griibler's  make  being  entirely  reliable. 


88       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

blood  parasites  in  general,  being  especially  useful  for  the  demon- 
stration of  the  malarial  parasites  and  the  filarial  embryos.  Thionin 
should  not  be  used  as  a  stain  for  films  in  which  the  general  mor- 
phology of  the  blood  cells  is  to  be  studied,  since  the  basophile 
granules  and  the  nuclei  are  the  only  histological  elements  for  which 
it  displays  any  decided  affinity.  Structures  reacting  toward  the 
dye  are  stained  violet  of  varying  degrees  of  intensity.  The  follow- 
faLrryC-Pe'  SUggCSted  by  Futcher  and  Lazear/  will  prove  satis- 

Thionin  

Absolute  alcohol  ..  .[[[  ..[ T°'3  gm- 

One  per  cent,  solution  of  carbolic  acid.".*.'.". qVs.  ad  100.0  c.c." 

Technic  of  Staining.—  Films  which  have  been  fixed  either 
chemically  or  by 'heat  are  stained  in  the  above  solution  for  from 
one  to  three  minutes,  being  then  washed  in  water,  dried  and 
mounted  as  usual.  The  best  results  are  obtained  by  using  the 
.trench  thionin,  made  by  Cogit  et  Cie,  of  Paris. 

Staining  with  Polychrome  Methylene-blue.— Goldhorn's 
solution  of  methylene-blue  and  lithium  carbonate  affords  a  rapidly 
acting  stain,  excellent  for  the  demonstration  of  the  finer  structure 
of  the  malarial  parasite  in  every  phase  of  its  development  In 
addition  to  giving  crisp,  clear-cut  pictures  of  the  chromatin  of  this 
organism,  the  solution  also  brings  out  distinctly  the  granular 
degeneration  of  the  erythrocytes,  the  nuclear  characteristics  of 
the  erythroblasts  and  leucocytes,  the  basophile  granules,  and  all 
ordinary  bacteria. 

.  Tefnfc  of  Staining.- -The  films  are  fixed  for  fifteen  seconds 
m  methyl  alcohol,  rinsed  in  water,  and  then  stained,  unheated, 
tor  trom  one  to  two  minutes,  after  which  they  are  thoroughly 
washed  m  running  water,  dried  without  the  use  of  heat,  and 
mounted  m  balsam.  Preliminary  staining  for  ten  or  fifteen  sec- 
onds with  a  o.i  per  cent,  aqueous  solution  of  eosin,  followed  by 
washing  gives  a  picture  in  which  the  contrast  between  the  plasma 
and  the  basic  elements  of  the  cells  is  clearly  differentiated.  Poly- 
chrome methylene-blue,  prepared  according  to  Goldhorn's  for- 
mula, is  sold  by  dealers  in  laboratory  supplies,  or  it  may  be  made 
m  this  manner: 

Two  grams  of  methylene-blue  are  dissolved  in  300  c  c  of 
warm  water  and  4  gm.  of  lithium  carbonate  are  added,  with 
constant  agitation.  The  mixture  is  poured  into  an  uncovered  por- 
celain capsule,  which  is  heated  over  a  shallow  water-bath  for  ten  or 

1  Johns  Hopkins  Hosp.  Bull.,  1899,  vol.  x,  p  70 
Ibid.,  1899,  vol.  x,  p.  70;  also  N.  Y.  Univ.  Bull,  of  Med.  Sci.,  1901,  vol.  i, 


MICROSCOPICAL  EXAMINATION  OF  STAINED  SPECIMEN.  89 

fifteen  minutes,  being  frequently  stirred  with  a  glass  rod.  After 
removal  from  the  water-bath  the  fluid  is  bottled,  without  filtering, 
and  set  aside  for  several  days,  after  which  its  reaction  is  cor- 
rected by  the  cautious  addition  of  a  5  per  cent,  acetic  acid  solu- 
tion until  the  dye  is  but  very  faintly  alkaline.  Should  the  solution 
become  too  alkaline  after  having  been  kept  for  some  time,  its  reac- 
tion may  be  corrected  by  adding  a  small  quantity  of  acetic  acid, 
as  in  the  preparation  of  the  original  mixture. 

A  differential  count  of  the  leucocytes  consists 
Differential  in  determining,  by  microscopical  examination  of 
Counting,     the  stained  specimen,  the  relative  percentages  of 
the  different  varieties  of  these  cells,  the  estimate 
being  based  upon  a  count  of  several  hundred  cells,  which  are  . 
classified  according  to  the  several  forms  described  in  a  following 
section  (Section  IV).    This  procedure,  by  means  of  which  quali- 
tative changes  affecting  the  leucocytes  may  be  detected,  is  ob- 
viously a  most  important  step  in  every  blood  examination,  and 
one  which  should  not  be  regarded  as  of  secondary  importance  to 
the  numerical  estimate  with  the  hemocytometer. 

The  technic  of  differential  counting  consists  simply  in  exam- 
ining successive  microscopical  fields  until  at  least  500  leucocytes 
have  been  counted,  the  cells  in  each  field  of  vision  being  identified 
as  they  appear,  and  jotted  down  on  a  piece  of  paper  by  the  ob- 
server under  their  appropriate  class.  As  soon  as  the  requisite 
number  of  cells  has  been  counted,  the  percentages  of  the  different 
forms  are  calculated,  to  express  the  final  result.  For  the  exami- 
nation a  TVinch  oil-immersion  objective  is  practically  indispen- 
sable, for  to  any  but  the  skilled  worker  it  is  difficult,  if  not  some- 
times impossible,  to  distinguish  the  various  forms  of  leucocytes 
with  a  lower  magnification  than  this  lens  provides.  In  order  to 
be  certain  that  each  field  is  taken  in  accurate  succession  to  its 
neighbor,  the  slide  should  be  moved  across  the  visual  field  by  the 
aid  of  a  mechanical  stage;  systematic  examination  of  any  given 
area  of  the  specimen  is  well-nigh  an  impossibility  if  the  slide  is 
simply  laid  on,  or  clipped  to,  the  stage  of  the  microscope,  and 
pushed  across  it  with  the  fingers  alone. 

If  nucleated  erythrocytes  are  found  in  the  specimen,  it  is 
equally  important  to  include  them  also  in  the  differential  count, 
classifying  them  into  two  histological  divisions,  normoblasts  and 
megaloblasts.  In  calculating  the  number  of  these  cells,  it  is 
obviously  impossible  to  employ  any  direct  method,  so  that  the 
estimate  must  of  necessity  be  more  or  less  approximate,  since  it 
is  based  upon  the  ratio  of  erythroblasts  to  a  given  number  of 
leucocytes.    Having  first  counted  the  latter  with  the  hemocytom- 


90       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


eter  the  number  of  nucleated  erythrocytes  is  noted  in  an  area 
ol  the  stained  specimen  in  which  a  fixed  number  of  leucocytes 
is  contained,  and  having  ascertained  these  data,  the  estimate  is 
made  according  to  the  formula: 

Number  of  erythroblasts  Number  of  leucocytes 

counted  tn  the stained  film    x  per  c.mm.  _  Number    of  erythro- 

N umber  of  leucocytes  counted  in  the  stained  film  blasts  per  c.mm. 

For  example,  in  a  case  of  pernicious  anemia  in  which  the  leu- 
cocytes number  4000  per  c.mm.,  and  a  total  of  35  erythroblasts 
is  noted  while  counting  1000  leucocytes  in  the  stained  film,  the 
calculation  is  as  follows  : 

35  X  4000  -=-  1000  =  140  erythroblasts  per  c.mm. 

Whenever  erythroblasts  are  found,  it  is  important  to  determine 
their  number  to  the  c.mm.  of  blood,  and  should  normoblasts  and 
megaioblasts  both  occur,  to  estimate  the  ratio  between  these  two 
types  of  cells. 


V.  COUNTING  THE  BLOOD  PLAQUES. 

Determann's  method 1  of  indirectly  estimating  the  number  of 
plaques  to  the  c.mm.  of  blood  is  both  simple  and  accurate  It 
consists  briefly,  in  first  determining  the  ratio  of  these  elements  to 
the  erythrocytes,  which  are  then  counted,  to  furnish  the  basis  for 
the  final  calculation. 

In  obtaining  the  blood,  a  drop  of  the  diluting  fluid  is  placed 
upon  the  patient's  finger  and  the  puncture  made  through  it  in 
order  that  the  blood,  as  it  flows  from  the  puncture,  will  instantly 
mix  with  the  diluent  without  coming  in  contact  with  the  air. 
I  he  blood  and  diluent  are  then  thoroughly  mixed  for  a  few  mo- 
ments by  the  aid  of  a  cover-glass,  after  which  a  small  portion  of 
the  mixture  is  transferred  to  a  Thoma-Zeiss  counting  chamber 
and  the  ratio  of  plaques  to  erythrocytes  determined  under  the 
microscope.    In  the  healthy  adult  this  ratio,  according  to  Deter- 
mann,  ranges  from  1  to  18  to  1  to  30,  averaging  about  1  to  22. 
With  another  drop  of  blood  the  erythrocyte  count  is  then  made 
by  the  usual  method,  and  the  actual  number  of 'plaques  to  the 
c.mm.  of  undiluted  blood  calculated  from  the  figure  thus  obtained 
For  example,  in  a  given  specimen  of  blood  in  which  the  ratio  of 
plaques  to  erythrocytes  is  found  to  be  1  to  25,  the  count  of  the 
latter  cells  being  5,000,000,  the  actual  number  of  plaques  is  there- 
fore 200,000  per  c.mm. 

1  Deutsch.  Arch.  f.  klin.  Med.,  1899,  vo1-  lxi,  p-  365. 


ESTIMATION  OF  CORPUSCLES  AND  PLASMA.  9 1 

The  diluents  for  which  Determann  expresses  a  preference  are 
either  a  9  per  cent,  aqueous  solution  of  sodium  chlorid  to  which 
a  little  methyl- violet  has  been  added,  or  an  aqueous  solution  con- 
taining one  per  cent,  of  sodium  chlorid  and  5  per  cent,  of  po- 
tassium bichromate.  Brodie  and  Russell1  recommend  equal 
parts  of  dahlia-glycerin  and  a  two  per  cent,  aqueous  solution  of 
sodium  chlorid. 

Any  of  the  diluting  fluids  already  mentioned  are  also  suit- 
able for  the  purpose. 

VI.  ESTIMATION  OF  THE  RELATIVE  VOLUMES  OF 
CORPUSCLES  AND  PLASMA. 

The  use  of  centrifugal  force  for  the  purpose  of  determining  the 
relative  volumes  of  blood  corpuscles  and  plasma  was  first  applied 
in  a  practical  manner  by  Hedin,2  who  embodied  the  earlier  ideas 
of  Blix  in  an  instrument  known  as  the  hematocrit.  More  re- 
cently Daland,3  by  improving  the  mechanical  construction  of  the 
original  instrument  and  by  simplifying  the  technic  of  using  ^  it, 
has  made  centrifugalization  of  the  blood  a  method  of  investigation 
adapted  to  general  clinical  work.  By  the  use  of  the  hematocrit 
a  pair  of  capillary  glass  tubes  filled  with  undiluted  blood  are  ro- 
tated in  their  horizontal  axes  at  a  high  rate  of  speed  until,  as  the 
result  of  the  centrifugal  force  thus  applied,  the  corpuscular  and 
liquid  portions  of  the  blood  become  separated,  the  former  being 
distinguishable  in  the  lumen  of  the  tube  as  a  column  the  length 
of  which  is  dependent  upon  the  volume  which  the  corpuscles  con- 
stitute in  relation  to  the  rest  of  the  blood  mass. 

This  instrument  (Fig.  30)  is  composed  of  a 
Daland's     set  of  cog-wheels  inclosed  in  a  metal  box  and 
Hematocrit,  geared  in  such  a  manner  as  to  cause  10,000 
revolutions  a  minute  of  a  vertical  spindle,  by 
turning  a  handle  at  a  definite,  uniform  rate  of  speed.    A  metal 
frame,  which  may  be  securely  fastened  to  the  spindle  by  a  modi- 
fied bayonet-lock,  carries  a  pair  of  capillary  glass  tubes,  each 
of  which  fits  into  two  cup-like,  rubber-lined  depressions,  and 
is  adjusted  and  held  in  place  by  a  spring.    Each  tube  measures 
50  mm.  in  length  with  a  lumen  of  0.5  mm.,  and  has  engraved  upon 
its  outer  surface  a  scale  representing  100  equal  divisions,  the  glass 

1  Jour.  Physiol.,  1897,  vol.  xxi,  p.  390. 

2  Skandinavisch.  Arch.  f.  Physiol.,  1890,  vol.  ii,  p.  134. 

3  University  Med.  Mag.,  1891,  vol.  iv,  p.  85;  also  Edwards'  supplement  to 
Keating's  "  Cyclopedia  of  the  Diseases  of  Children,"  Philadelphia,  1899,  vol.  v, 
P-  537- 


92       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

immediately  above  the  scale  being  molded  so  as  to  form  a  lens- 
front,  to  magnify  the  column  of  blood  and  to  facilitate  the  reading 

?f  ^Ldl71S1^'    i  bit  0fnrubber  tubin§  fitted  with  a  mouthpiecf 
s  used  for  filling  the  capillary  tube,  in  the  same  manner  in  which 
the  blood  is  measured  with  the  hemocytometer.    While  in  use 
the  instrument  is  securely  attached  to  the  projecting  edge  of  a 

mV/i  h7r  m™£S  °f  a  damP  °Perated  ^  a  thumb-Lew. 
Method  of  ^.-Having  cleaned  and  punctured  the  patient's 
nnger  in  the  usual  manner,  the  beveled  end  of  one  of  the  capil- 
ary  tubes  is  immersed  in  the  drop  of  blood,  which  is  sucked  up 
the  lumen  of  the  tube  until  it  is  exactly  filled.    The  forefinger, 

smeared  with  a  little  vaselin,  is  then 
applied  to  the  beveled  end  of  the  tube, 
while  the  rubber  suction  tube  is  care- 
fully removed  by  twisting  it  free— not 
by  forcibly  pulling  it  off,  since  this  may 
accidentally  cause  removal  of  a  portion 
of  the  blood  column  by  suction.  The 
tube  thus  charged  with  blood  is  at  once 
adjusted  to  one  arm  of  the  frame,  and 
the  empty  tube  similarly  fixed  in  the 
other  arm,  to  equalize  the  balance,  this 
step  being  completed  as  rapidly  as  pos- 
sible, in  order  to  anticipate  coagulation. 
When  the  tubes  have  been  thus  ad- 
justed, and  the  frame  securely  locked 
in  the  spindle,  the  handle  of  the  in- 
strument is  turned  for  three  minutes1  at 
the  rate  of  77  revolutions  a  minute,  this 
rate  of  speed  securing  10,000  rotations 
a  minute  of  the  frame,  since  the  latter 
revolves  130  times  with  each  complete  turn  of  the  handle.  The 
centrifugalization  having  been  finished,  the  charged  tube  is  care- 
fully removed  from  the  frame,  and  held  against  a  piece  of  dull 
white  paper,  so  that  the  height  of  the  blood  column  may  be  easily 
determined.    In  order  to  make  the  reading  with  accuracy,  it  is 
sometimes  necessary  to  use  a  small  magnifying  glass,  for  the 
divisions  on  the  scale  of  the  tube  are  but  0.5  mm.  apart— a 
distance  too  small  to  judge  easily  with  the  naked  eye.    On  ex- 
amination, three  distinct  divisions  of  the  lumen  of  the  tube 
containing  the  centrifugalized  blood  may  be  distinguished  :  first, 

1  In  a  recent  personal  communication  Dr.  Daland  advises  that,  in  order  to 
f    £°St  acc?ra*e  rfefults  with  his  instrument,  the  centrifugalization  be  con- 
tinued  for  three,  instead  of  for  two,  minutes,  as  he  formerly  recommended 


Fig.  30. — Daland's  Hematocrit. 


ESTIMATION  OF  CORPUSCLES  AND  PLASMA. 


93 


a  dark-colored  column  consisting  of  erythrocytes,  reaching,  in 
normal  blood,  to  a  point  between  the  divisions  marked  50  and  51  ; 
second,  a  thin  layer  of  leucocytes,  showing,  in  blood  in  which 
these  cells  are  not  largely  increased,  as  an  indistinct,  milky  stratum 
overlying  the  erythrocytes  ;  and,  third,  a  layer  of  clear  plasma 
occupying  the  remainder  of  the  lumen.  The  normal  volume  of 
erythrocytes  being  arbitrarily  regarded  as  100  per  cent.,  to  com- 
pute this  result  the  figure  of  the  scale  to  which  these  cells  rise  is 
multiplied  by  two.  Unless  the  leucocytes  are  greatly  increased 
in  number,  the  layer  formed  by  these  cells  is  too  delicate  and  too 
dully  defined  to  be  read  with  any  degree  of  accuracy  ;  but  in 
cases  of  high  leucocytosis  and  of  leukemia  it  is  quite  possible  to  es- 
timate roughly  the  relative  proportions  of  leucocytes  to  erythro- 
cytes. 

The  capillary  tube  which  has  been  rilled  with  blood  should  be 
cleaned  as  soon  after  use  as  possible,  water,  followed  by  alcohol 
and  ether,  being  used  for  this  purpose.  A  fine  wire  should  be 
passed  through  its  lumen,  to  dislodge  any  obstruction  which  may 
result  from  drying  of  the  column  of  closely  packed  corpuscles. 

The  hematocrit,  if  its  clinical  application  is  limited  to  the  de- 
termination simply  of  the  relative  volumes  of  the  blood  corpus- 
cles and  plasma,  may  be  relied  upon  to  furnish,  on  the  whole, 
dependable  information,  the  necessary  errors  attending  its  use 
probably  being  within  two  per  cent.    It  is  also  useful  in  the  study 
of  hemoglobinemia,  cholemia,  and  lipemia.    If  employed  in  the 
role  of  a  hemocytometer,  however,  its  results  must  needs  be  highly 
inaccurate,  just  in  those  instances  in  which  exact  methods  of 
investigation  are  all  important.    It  is  true  that  in  normal  blood, 
in  which  the  size  of  the  corpuscles  ranges  within  the  physiologi- 
cal limits,  it  is  correct  to  consider  each  percentage  volume  as 
representing  approximately  a  count  of  100,000  erythrocytes  per 
c.mm.    In  blood  characterized  by  any  considerable  deformity 
in  the  size  and  shape  of  these  cells,  as  in  high-grade  anemia 
or  in  leukemia,  it  is  perfectly  obvious  that  no  such  corres- 
pondence between  the  count  and  the  percentage  volume  can  be 
expected — blood  in  which  microcytosis  is  pronounced  is  certain 
to  show  a  lower  percentage  volume  of  erythrocytes  than  blood  in 
which  megalocytosis  prevails,  or  than  blood  containing  normal- 
sized  cells,  although  the  counts  of  all  three  may  be  identical.  Simi- 
larly, a  given  number  of  lymphocytes  should  indicate  a  lower  per- 
centage volume  than  an  equal  number  of  myelocytes,  or  even 
polynuclear  neutrophiles.    On  account  of  these  sources  of  fallacy, 
if  for  no  other  reason,  the  hematocrit  estimate  should  never  be 
taken  as  a  basis  for  calculating  the  count  in  pathological  condi- 


94       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


tions  in  lieu  of  the  more  accurate,  if  more  laborious,  method  of 
counting  the  corpuscles. 

Capps1  considers  that  the  hematocrit  may  be  used  to  advan- 
tage m  conjunction  with  the  hemocytometer,  in  determining  the 
actual  size  or  volume  of  the  individual  erythrocyte,  and  he  regards 
this  method  as  far  more  reliable  than  the  use  of  the  micrometer 
since  with  the  latter  only  the  transverse  diameter  of  the  cells,  and 
not  their  depth  can  be  measured.  The  formula  for  calculating 
this    volume  index    has  been  given  elsewhere.    (Seep  173) 


VII.  ESTIMATION  OF  THE  SPECIFIC  GRAVITY. 
This  method  , of  investigation  is  used  as  an  indirect  means  of 
computing  the  percentage  of  hemoglobin,  owing  to  the  more  or 
less  constant  parallelism  maintained  between  it  and  the  specific 
gravity  of  the  whole  blood.  The  correspondence  between  the  two 
together  with  the  sources  of  error  inseparable  from  the  test,  has 
been  pointed  out  in  another  section.    (See  p.  133.) 

Hammerschlag's    modification2    of  Roy's 
Hammer-      method3  of  determining  the  specific  gravity  of 
schlag  s      the  blood  best  serves  the  purpose  of  those  who 
Method.      choose  this  roundabout  means  of  approximating 
the  hemoglobin  percentage.    It  consists  in  first 
making  a  mixture  of  benzol  and  chloroform  of  such  a  specific 
gravity  that  a  small  drop  of  blood  deposited  in  the  liquid  remains 
suspended,  after  which  the  specific  gravity  of  the  mixture  is  de- 
termined with  a  hydrometer,  the  figure  thus  obtained  representing 
the  density  of  the  blood  used  in  the  test.    The  hemoglobin  per 
centage  corresponding  to  this  figure  is  then  selected  from  a  table 
giving  the  various  degrees  of  blood  densities  and  the  percentages 
01  hemoglobin  to  which  they  are  equivalent. 

The  apparatus  required  for  making  the  test  includes  a  hy- 
drometer provided  with  a  scale  graduated  to  1.070,  a  hydrometer 
jar  having  a  wide,  substantial  base,  a  glass  capillary  tube,  and  a 
glass  shrrmg  rod.  An  ordinary  urinometer  may  be  used  instead 
??T  hvdrometer,  since  specific  gravities  in  excess  of  1.060 
(the  highest  gradation  on  the  scale  of  most  urinometers)  are  not 
often  encountered.  More  accurate  results,  however,  are  possible 
with  a  standardized  instrument.    Levy4  has  shown  that  with  an 

1  Jour.  Amer.  Med.  Assoc.,  1900,  vol.  xxxvi,  p.  464, 
Zeitschr.  f.  klin.  Med.,  1892,  vol.  xx,  p.  444. 
Cited  by  Devoto,  Zeitschr.  f.  Heilk.,  1889,  vol.  xi,  p.  17c 
Lancet,  1903,  vol.  i,  p.  1302 


ESTIMATION  OF  THE  SPECIFIC  GRAVITY. 


95 


ordinary  hydrometer  an  excessive  reading,  ranging  from  3  to  (io 
degrees,  always  occurs,  owing  to  the  disturbing  effect  upon  the  in- 
strument of  the  low  surface  tension  of  the  chloroform-benzol  mix- 
ture. To  obtain  accurate  figures  it  is  necessary  to  use  a  hydrome- 
ter which  has  been  standardized  to  these  reagents.  Either  a 
Thoma-Zeiss  leucocytometer  or  a  medicine  dropper,  the  free  end 
of  which  should  be  heated  in  a  flame  and  bent  into  an  obtuse 
angle,  will  serve  as  a  capillary  pipette. 

Benzol  and  chloroform  are  mixed  together  in  the  hydrometer 
jar  in  such  proportions  that  the  specific  gravity  of  the  liquid^  is 
approximately  equal  to  that  of  normal  blood,  1.060.  This  mix- 
ture having  been  made  and  its  specific  gravity  taken,  the  point  of 
the  capillary  pipette,  charged  with  blood,  is  plunged  beneath  the 
surface  of  the  liquid  and  a  small  bead  of  blood  gently  expelled. 
If  the  blood  drop  rises  to  the  surface  of  the  mixture,  a  few  drops 
of  benzol  are  added,  while  if  it  sinks  to  the  bottom  of  the  jar, 
chloroform  is  used,  the  addition  of  the  appropriate  reagent  being 
continued  until  the  drop  neither  rises  nor  sinks,  but  remains  sta- 
tionary, suspended  in  the  mixture.  When  this  point  has  been 
determined,  the  specific  gravity  of  the  liquid  is  taken  by  means  of 
the  hydrometer,  this  figure  obviously  representing  the  specific 
gravity  of  the  blood  drop  itself.  To  convert  the  specific  gravity 
into  its  hemoglobin  equivalent  the  figure  obtained  by  the  above 
procedure  is  compared  with  one  of  the  tables  given  on  page  133. 
After  each  addition  of  benzol  or  of  chloroform  the  contents  of  the 
jar  must  be  thoroughly  mixed  by  stirring  with  the  glass  rod,  in 
order  to  secure  uniformity  in  the  density  of  the  liquid.  The  latter, 
if  it  is  filtered  free  from  blood  and  preserved  in  a  tightly  stop- 
pered bottle,  may  be  used  again  in  subsequent  tests. 

In  spite  of  the  enthusiasm  evinced  by  certain  authors  for  this 
method  of  obtaining  hemoglobin  values,  considerable  experi- 
ence with  the  test  has  convinced  the  writer  that  it  is  both  crude 
and  untrustworthy— it  is  useful,  no  doubt,  when  a  hemometer 
cannot  be  obtained,  but  in  no  sense  is  it  an  efficient  substitute  for 
colorimetric  methods.  The  liability  of  the  blood  drop  to  split 
up  into  numerous  fine  particles,  to  adhere  to  the  inside  of  the 
jar,  and  to  become  altered  in  composition  from  the  influence  of  the 
reagents,  as  well  as  the  tedious  attempts  which  must  usually  be 
made  to  add  just  the  proper  quantities  of  benzol  and  chloroform 
to  secure  a  mixture  in  which  the  drop  neither  sinks  nor  rises,  are 
a  few  of  the  drawbacks  which  must  make  the  test  unpopular  with 
busy  clinicians.  For  a  critical  review  of  the  clinical  value  of 
Hammerschlag's  test  Baumann's  article1  should  be  consulted. 
1  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  473. 


96       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


VIII.  ESTIMATION  OF  THE  ALKALINITY. 

A    convenient    clinical    method    of  deter- 
Engel's      mining  the  alkalinity  of  the  blood  is  by  the  use 
Alkalimeter.  of  Engel's  alkalimeter  (Fig.   31).    By  means 
of  this  instrument  a  measured  quantity  of  fresh 
blood  is  diluted  with  distilled  water  in  the  proportion  of  one  to 
ten,  and  then  titrated  with  a  TV  normal  solution  of  tartaric  acid 
until  the  mixture  reacts  with  lacmoid  paper,  the  total  alkalinity 
being  calculated  from  the  amount  of  the  tartaric  acid  used.  The 
methods  of  alkalinity  estimation  devised  by  Landois,1  by  Lieb- 
reich,2  by  Haycraft  and  Williamson,3  by  Wright,4  and  by  Kraus5 
are  not  well  adapted  to  routine  blood  work,  being  either  too  com- 
plicated and  elaborate  for  such  a  purpose  or  too  inaccurate. 

The  apparatus  which  Engel  has  devised  consists  of  the  follow- 
ing parts:  a  diluting  and  mixing  pipette,  resembling  a  large-sized 
Thoma-Zeiss  erythrocytometer;  a  graduated  burette  by  means  of 
which  the  amount  of  tartaric  acid  solution  used  in  the  test  is  meas- 
ured; a  glass  cylinder  in  which  the  titration  is  made;  and  a  glass 
stirring  rod.  The  mixing  pipette  is  graduated  in  three  principal 
divisions  marked  0.025,  0.05,  and  5.0  respectively,  the  first  two 
divisions  being  further  scaled  in  tenths  by  fine  horizontal  mark- 
ings; otherwise  the  instrument  is  modeled  like  a  blood-counting 
pipette^  The_  burette  has  a  capacity  of  5  cc,  and  is  provided  with 
a  scale  indicating  100  equal  divisions;  when  in  use,  it  is  clamped  up- 
right, by  means  of  a  special  attachment,  to  a  vertical  brass  support 
which  screws  into  a  fitting  in  the  box  containing  the  apparatus. 

Method  0}  Use.— The  technic  of  using  the  alkalimeter  is  simple 
and  time  saving  in  comparison  with  that  required  by  other  well- 
known  methods  of  alkalinity  testing.  Finger-blood,  obtained  by  a 
rather  deep  puncture,  so  as  to  afford  a  good-sized  drop,  is  sucked 
up  in  the  pipette  until  it  reaches  the  mark  0.05,  immediately  after 
which  distilled  water  is  similarly  drawn  up  the  lumen  of  the  tube 
until  the  mixture  of  blood  and  water  fills  the  bulbous  expansion 
and  reaches  the  mark  5.0  in  the  constricted  portion  beyond. 
While  sucking  up  the  water  the  pipette  should  be  rapidly  twisted 
to  and  fro  between  the  thumb  and  forefinger,  to  insure  thorough 
mixing  of  the  blood  and  water  as  they  together  fill  the  expanded 
portion  of  the  instrument.  As  soon  as  the  dilution  has  been 
made,  the  pipette  should  be  shaken  for  a  minute  or  so,  until  the 

1  Real-Encyclop.,  1885,  v°l-  iii,  p.  161. 

2  Berichte  d.  deutsch.  chem.  Gesellsch.,  1868,  vol.  i,  p.  48. 
Proc.  Roy.  Soc,  Edinburgh,  June  18,  1888. 

4  Lancet,  1897,  vol.  ii,  p.  719.  5  Zeitschr.  f.  Heilk.,  1889,  vol.  x,  p.  106. 


ESTIMATION  OF  THE  ALKALINITY. 


97 


mixture  becomes  of  a  uniform  "laky"  tint,  which  indicates  that 
all  the  hemoglobin  has  been  dissolved  from  the  corpuscular 
stroma.  The  contents  of  the  pipette  are  blown  out  into  the  glass 
cylinder,  which  is  placed  beneath  the  faucet  of  the  burette,  the 
latter  having  been  previously  rilled  to  the  mark  o  with  a  TV  nor- 
mal solution  of  tartaric  acid.  By  turning  the  stop-cock  of  the 
burette  the  test  solution  is  now  added,  drop  by  drop,  stirring  be- 
tween each  addition,  to  the  measured  amount  of  diluted  blood 
in  the  cylinder.    From  time  to  time  a  drop  of  the  mixture  is  re- 


Fig.  31. — Engel's  Alkalimeter. 


moved  by  means  of  the  glass  rod  and  tested  with  the  lacmoid 
paper,  the  titration  being  continued  until  the  reaction,  recognized 
as  a  bright-red  halo  which  forms  around  the  edge  of  the  drop,  is 
obtained.  The  titration  is  then  stopped,  and  a  note  made  of  the 
number  of  drops  of  the  test  solution  which  have  been  used.  In 
normal  blood  the  writer  finds  that  from  9  to  11  drops  are  re- 
quired to  give  the  reaction.  The  estimate  of  the  total  alkalin- 
ity of  the  blood  is  made  by  multiplying  by  the  figure  53.3  the 
number  of  drops  of  the  tartaric  acid  solution  used,  according  to 
7 


98       EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


the  formula,  10  :  aw  533.0  :x,  a  representing  the  drops  of  the 
reagent.1  The  result  thus  obtained  is  expressed  in  milligrams  of 
NaOH  per  100  c.c.  of  blood.  The  following  table  maybe  useful 
for  reference  in  determining  the  various  degrees  of  alkalinity: 

6  drops  of  the  solution  are  used,  the  alkalinity  equals  319  mgm.  NaOH 


9 
10 
11 
12 
13 
14 


373 
436 
479 
533 
586 

639 
692 
746 


After  use  the  pipette  should  be  thoroughly  washed  out  with 
water,  alcohol,  and  ether,  and  then  dried,  in  the  manner  already 
directed  for  cleaning  the  Thoma-Zeiss  instrument. 

This  ingenious  instrument2  is  used  in  con- 
D  are's       nection  with  a  spectroscope,  its  principle  depend- 
Hemo-alkalim-  ing  upon  the  dissipation  of  the  absorption  bands 
eter.        of  oxyhemoglobin  when  exact  neutralization  of 
the  blood  ensues,  after  the  addition  of  a  2  <jVo  nor- 
mal solution  of  tartaric  acid.    The  working  parts  of  the  apparatus 
are  explained  by  the  accompanying  illustration  (Fig.  32) .    The  test 
solution  to  be  employed  is  made  up  as  follows: 

Acid,  tartaric.  (Merck's  reagent)  gr.  j  (0  075  gm  ) 

Alcohol  ^v(2o  c.c). 

Aquadestil  q.  s.  gvj  (200  c.c). 

Method  of  Use.— The  alkalimeter  tube  (Fig.  32,  A),  fitted  with 
its  blood  pipette,  B,  is  held  horizontally,  and  the  pipette  filled 
with  blood  by  presenting  its  exposed  end  to  the  drop  as  it  flows 
from  the  puncture.  With  an  ordinary  medicine  dropper  containing 
distilled  water  and  coupled  to  the  blood  pipette  by  a  bit  of  rubber 
tubing,  the  measured  blood  is  washed  into  the  alkalimeter  tube 
until  the  point  o  is  reached.  Now,  with  the  thumb  closing  the 
opening,  C,  in  its  bulb,  the  alkalimeter  tube  is  inverted  several  times, 
in  order  to  mix  the  blood  and  water.  The  reagent  pipette,  D,  is 
filled  with  the  test  solution,  connected  by  tubing  with  the  free  end 

1  Assuming  that  0.5  c.c.  of  tartaric  acid  is  used  to  neutralize  0.05  c.c.  of  blood, 
therefore  for  every  100  c.c.  of  blood  1000  c.c,  or  one  liter,  of  a  7\  normal  solution  of 
tartaric  acid  are  required.  As  the  alkalinity  of  the  blood  is  not  expressed  by  the 
amount  of  acid  necessary  to  saturate  it,  but  in  milligrams  of  an  alkali,  sodium  hy- 
drate, the  calculation  is  made  thus:  as  the  equivalent  weight  of  tartaric  acid  is  75, 
and  that  of  sodium  hydrate  40,  one  liter  of  water  dissolving  75  gm.  of  the  former 
saturates  40  gm.  of  the  latter— that  is,  one  liter  of  a  Y\  normal  tartaric  acid  solution 
saturates  gm.,  or,  in  other  words,  533  mgm.,  of  sodium  hvdrate,  this  figure 
being  taken  by  Engel  as  the  degree  of  normal  alkalinity  of  the  blood. 
Phila.  Med.  Jour.,  1903,  vol.  xi,  p.  137. 


ESTIMATION  OF  THE  ALKALINITY. 


99 


of  the  blood  pipette,  and  compressed  so  as  to  force  the  reagent 
into  the  diluted  blood  within  the  alkalimeter  tube.  In  doing  this 
it  is  necessary  to  thumb  the  opening  in  the  bulb  of  the  latter,  to 
avoid  the  mixture  of  the  blood  and  reagent.  The  tube  and  reagent 
pipette,  still  connected,  are  now  grasped  and  inverted,  to  mix  thor- 
oughly the  contents  of  the  former,  after  which  a  preliminary 
observation  is  made  by  adjusting  the  lower  part  of  the  tube 
(below  the  mark  o)  to  the  cleft  of  a  Browning  pocket  spectroscope. 
If  the  oxyhemoglobin  absorption  bands  per- 
sist, more  of  the  reagent  is  added,  drop  by 
drop,  inverting  the  tube  between,  and  exam- 
ining with  the  spectroscope  after,  each  drop. 
When  the  bands  disappear,  the  figure  to  which 
the  neutralized  blood  solution  reaches  is  noted, 
and  compared  with  the  table  of  equivalents  given 
below,  to  obtain  the  final  result,  which  is  ex- 
pressed in  milligrams  of  NaOH  per  100  c.c. 
of  blood.  The  figure  for  normal  blood  with 
this  instrument  is  266. 

TABLE  OF  EQUIVALENTS. 


Cubic  Centimeters  of 
Reagent. 

2.6  

2-4  


Mgm.  of  NaOH  to 
100  c.c.  of  Blood. 

 345 -o 

 3i9-o 


2.2  292.0 

2.0  266.0 


1.8. 
1.6. 
1.4. 
1.2 . 


■  -  239.0 

  212.0 

'■.  .176.0 

 159-° 

i-o  133-0 

0.8   96.0 

0.6   79.0 

o-4   53-o 

0.2   26.6 


Fig.  32. — Dare's  Hemo- 

alkalimeter. 
A,  Alkalimeter  tube;  B, 
automatic  blood  pi- 
pette; C,  opening  for 
the  admission  of  air: 
D,  reagent  pipette. 


While,  up  to  the  present  time,  it  cannot  be 
claimed  that  information  of  any  real  diagnostic 
pertinence  has  been  obtained  from  the  study  of 
the  alkalinity  of  the  blood,  this  procedure  should 
prove  of  value  in  the  systematic  investigation  of  many  cases, 
especially  those  of  high-grade  anemia.  As  elsewhere  mentioned, 
the  degree  of  normal  blood  alkalinity  varies  greatly  according  to 
the  particular  method  by  which  this  .figure  is  ascertained,  so  that 
it  follows  that  the  results  obtained  by  means  of  one  apparatus 
cannot  be  compared  with  those  based  upon  investigation  with 
another  instrument  of  different  design. 


IOO     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


IX.    DETERMINATION  OF  THE  RAPIDITY  OF 
COAGULATION. 

This  procedure  is  useful  in  the  study  of  such  conditions  as 
icterus,  purpura,  hemophilia,  scurvy,  various  specific  infections, 
and  other  diseases  characterized  by  abnormalities  in  the  clotting 
time  of  the  blood.  Knowledge  of  how  long  it  takes  a  given  blood 
to  clot  not  only  adds  completeness  to  the  clinical  history,  but 
allows  the  physician  to  judge  of  the  effect  of  remedies  administered 
with  a  view  to  promoting  coagulation.  No  careful  surgeon  to- 
day neglects  to  test  the  patient's  blood  coagulability  before  operat- 
ing for  the  relief  of  obstructive  lesions  of  the  biliary  passages.  No 
physician  should  omit  to  make  repeated 
coagulation  tests  in  treating  one  of  the 
hemorrhagic  diatheses  or  a  primary  ane- 
mia. 

|  The  coagulation  time 

Glass  Slide  may  be  determined  ap- 
1  Method.     proximately  by  collecting 

£|  several  individual  drops 

I  H      of  blood  of  the  same  size  upon  the  surface 

fflk  W      of  a  perfectly  clean,  slightly  warmed  glass 

1  slide.  At  regular  intervals  of  about  one 
minute  a  straw  of  a  whisk-broom  is  lightly 
trailed  through  each  drop  in  succession, 
until  sooner  or  later  a  delicate  thread  of " 
fibrin  may  be  observed  clinging  to  the 
straw.  The  period  which  has  elapsed 
between  the  deposit  of  the  blood  on  the 
slide  and  the  appearance  of  this  indica- 
tion of  clotting  is  expressed  in  minutes, 
to  represent  the  coagulation  time  of  the 
specimen  under  investigation.  Normal  blood  thus  treated  coagu- 
lates in  from  two  and  one-half  to  five  minutes. 

The  method  described  by  Milian1  is  perhaps  even  simpler.  A 
rather  large  drop  of  blood  is  collected  upon  the  center  of  a  clean, 
dry  glass  slide,  which,  after  the  lapse  of  a  minute  or  so,  is  carefully 
tilted  to  a  vertical  plane.  With  the  slide  held  in  this  position  the 
profile  of  the  coagulated  drop  forms  a  symmetrical,  mound-like 
convexity,  while  that  of  the  incompletely  clotted  drop  is  tear- 
shaped  (Fig.  33).  The  time  elapsing  between  the  collection  of 
the  blood  drop  and  the  first-named  change  is  considered  the  coagu- 
lation time.    Five  minutes  is  the  average  period  for  normal  blood. 

1  Presse  med.,  1904,  vol.  i,  p.  202. 


A.  B. 

Fig.  33. — A.  Incomplete  Co- 
agulation.   Tear-shaped  drop 


B.  Complete 
Convex  drop. 


Coagulation. 


DETERMINATION  OF  THE  RAPIDITY  OF  COAGULATION.  IOI 

The  latest  model  of  this  instrument1  consists 
Wright's      of  a  tin  reservoir  fitted  with  a  removable  rack 
Coagulometer.  holding  a  thermometer  and  a  set  of  twelve 
calibrated  glass  coagulation  tubes.    For  filling 
the  latter  an  aspirator  tube  with  a  rubber  connection  is  employed. 
The  thermometer  indicates  degrees  of  the  Centigrade  scale,  and  is 


Fig.  34. — Wright's  Coagulometer. 


also  graduated  at  18. 50  and  at  370,  the  temperature  of  "half  blood 
heat"  and  of  " blood  heat,"  respectively.  The  coagulation  tubes, 
made  of  stout  glass,  are  furnished  with  tight  rubber  caps,  used  to 
seal  their  blunt  ends  when  immersed;  they  have  an  internal  di- 
ameter of  0.25  mm.,  and  are  marked  to  indicate  a  blood  column 
of  5  cc  Each  tube  is  numbered  to  correspond  with  its  appropriate 
place  in  the  rack  of  the  reservoir. 

1  Lancet,  1902,  vol.  ii,  p.  15. 


102     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

Method  oj  Use. — The  reservoir  is  filled  with  water  having  a 
temperature  of  18.50  C.,1  and  the  tubes,  each  fitted  with  a  rubber 
cap,  are  placed  in  the  rack,  sealed  end  downward,  where  they  are 
allowed  to  remain  immersed  for  a  few  minutes  until  they  acquire 
approximately  the  same  temperature  as  that  of  the  water.  They 
are  then  removed,  dried,  and  stripped  of  their  rubber  caps. 

Having  then  pricked  the  patient's  finger,  5  cc  of  blood 
are  sucked  up  each  tube,  at  successive  intervals  of  one  min- 
ute, a  tube  as  soon  as  filled  being  returned  to  its  appropriate 
place  in  the  reservoir.  It  is  not  necessary  to  replace  the  caps — 
the  tubes  are  simply  placed  point  downward  in  the  water,  the 
temperature  of  which  is  from  time  to  time  readjusted  to  the  stand- 
ard by  adding  hot  water  to  the  reservoir  as  its  contents  cool. 
After  the  lapse  of  an  appropriate  interval  the  tube  first  rilled  is  re- 
moved from  the  reservoir  and  tested  by  attempting  to  blow  out  its 
contents  upon  the  surface  of  a  piece  of  white  filter  or  blotting  paper. 
The  other  tubes  are  similarly  tested  in  rotation,  at  intervals  of  one 
minute  or  less,  until,  after  having  thus  tried  a  variable  number 
one  is  found  from  which  the  blood  cannot  be  expelled. 

Coagulation  may  then  be  considered  to  have  occurred,  the 
time  required  for  this  process  being  expressed  by  the  number  of 
minutes  elapsing  between  the  filling  of  the  tube  in  question  and 
the  evidence  of  clotting  thus  demonstrated.  With  normal  blood 
the  coagulation  time,  as  determined  by  this  instrument,  gener- 
ally ranges  from  about  three  to  six  minutes.  In  rare  instances 
Wright 2  found  that  in  the  healthy  male  adult  clotting  may  be  pro- 
longed for  fifteen  minutes. 

After  use,  a  fine  wire  should  be  forced  through  the  lumen  of 
the  tubes  to  dislodge  the  clots,  after  which  the  remaining  traces  of 
blood  are  to  be  removed  by  thorough  washing  with  distilled  water, 
alcohol,  and  ether,  in  the  order  named. 

X.  CRYOSCOPICAL  EXAMINATION. 

Cryoscopy  is  the  method  of  determining  the 
Cryoscopy.  freezing-point  of  a  given  liquid  and  the  com- 
parison of  this  figure  with  the  freezing-point  of 
distilled  water.  This  method  of  investigation  is  based  upon  the 
principle  that  the  freezing-point  of  any  liquid  is  proportionate  to  the 
number  of  its  contained  molecules.  The  greater  the  molecular 
concentration,  the  lower  the  point  at  which  the  fluid  freezes. 

1  In  slowly  coagulating  bloods  the  temperature  should  be  about  that  of  blood 
heat,  37°  C. 

2  Brit.  Med.  Jour.,  1902,  vol.  ii,  p.  1706. 


CRYOSCOPICAL  EXAMINATION. 


Cryoscopy  of  the  blood  and  urine  was  first  applied  to  clin- 
ical medicine  by  von  Koranyi,1  who  thus  was  able  to  determine 
the  status  of  the  renal  function.  The  average  freezing-point  of 
normal  blood  is  — 0.5 70  C,  ranging  between  — 0.560  and  — 0.580 
C.  Urine  in  the  healthy  individual  freezes  between  — o.o°  and 
— 20  C.  Venous  blood  freezes  at  a  slightly  lower  temperature 
than  arterial.  In  renal  disease  with  decided  insufficiency  of  the 
kidneys  it  is  found  that  the  freezing-point  of  the,  blood  is  lowered, 
while  that  of  the  urine  is  correspondingly  raised,  owing  to  the 
retention  in  the  blood  of  matter  which  the  crippled  kidneys  are 
unable  to  excrete.  Excision  of  one  kidney  does  not  disturb  the 
normal  freezing-points  of  the  blood  and  urine,  but  double  neph- 
rectomy promptly  lowers  that  of  the  former  and  raises  that  of  the 
latter. 

A  freezing-point  of  — o.6°  C.  or  lower  for  blood  and  of  i°  C. 
or  higher  for  urine  indicates  a  sufficient  degree  of  renal  impair- 
ment to  contraindicate  surgical  interference  in  lesions  of  the  kid- 
neys. This  dictum  was  first  expressed  by  Kiimmel,2  who  bases  it 
upon  an  experience  of  170  cases  of  renal  surgery  in  which  cryos- 
copy was  practised,  including  chronic  nephritis,  nephrolithiasis, 
tuberculosis,  cysts,  neoplasms,  pyonephrosis,  hydronephrosis,  and 
post-operative  anuria.  Rumpel's  extensive  researches3  in  300 
similar  cases  showed  that  in  normal  individuals  and  in  those 
with  unilateral  renal  lesions  the  blood  freezing-point  did  not  vary 
from  the  figures  given  above  ( — 0.560  to  — 0.5 8°  C),  while  in 
bilateral  lesions  of  the  kidneys  it  ranged  between  — 0.550  and 
— 0.810  C.  In  renal  disease  unaccompanied  by  uremia  Linde- 
mann4  found  no  variations  from  the  normal  freezing-point,  but 
with  the  onset  of  this  complication  the  blood  froze  at  a  point  as  low 
as  — 0.70  C. 

Koeppe's  data5  in  conditions  other  than  those  involving  the 
kidneys  are  of  interest.  He  found,  in  a  series  of  cases  including 
junctional  neuroses,  carcinoma,  diabetes,  pleurisy,  and  pneumonia, 
a  blood  freezing-point  varying  from — 0.50  to  — 0.630  C.  Similar 
figures,  of  theoretical  rather  than  practical  interest,  have  also  been 
determined  in  various  general  diseases  by  Ogston,6  Tinker,7  Tieken,8 

1  Zeitschr.  f.  klin.  Med.,  1897,  vol.  xxxiii,  p.  45;  ibid.,  1899,  vol.  xxxiv,  p.  1; 
Berlin,  klin.  Wochenschr. ,  1901,  vol.  xxxviii,  p.  424. 

2  Centralbl.  f.  Chir.,  1902,  vol.  xxix,  p.  121. 

3  Munch,  med.  Wochenschr.,  1903,  vol.  1,  pp.  19,  67,  and  117. 

4  Deutsch.  Arch.  f.  klin.  Med.,  1899,  vol.  lxv,  p.  1. 

5  Cited  by  Cattell,  Internat.  Clinics,  1904,  vol.  i,  p.  6. 

6  Lancet,  1901,  vol.  ii,  p.  1253. 

7  Johns  Hopkins  Hosp.  Bull.,  1903,  vol.  xiv,  p.  162. 

8  Med.  News,  1904,  vol.  lxxxiv,  p.  416. 


104  ^  EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

Ceconi,1  Sollmann,2  and  others.3  It  is  of  interest  to  note  that  the 
pregnant  woman's  blood  freezes  at  a  higher  temperature  than  nor- 
mal, but  that  the  latter  figure  is  reached  after  delivery,  as  the 
molecular  concentration  of  her  blood  rises.  In  diabetes  mellitus 
the  freezing-point  is  low,  but  in  pernicious  anemia  and  in  various 
forms  of  hydremia  it  is  high.  Inhalations  of  oxygen  lower  the 
figure,  but  in  conditions  of  cyanosis  with  an  excess  of  carbonic 
acid  in  the  blood  the  freezing-point  rises.  It  is  of  value  also  to 
observe  that  cystitis  and  pyelitis  do  not  affect  the  blood's  freezing- 
points. 

Carrara4  and  Revenstorf 5  found  that  in  cases  of  drowning  the 
resulting  dilution  of  the  blood  causes  radical  deviations  from 
the  normal  freezing-point,  which  rises  in  the  case  of  drowning 
in  fresh  water  and  falls  after  death  by  submersion  in  salt  water. 
In  this  connection  the  general  statement  applies,  that  the  freezing- 
point  of  the  diluted  blood  approaches  that  of  the  fluid  with  which 
the  body  is  waterlogged.  Whether  the  deviation  be  plus  or  minus, 
it  is  generally  more  marked  in  the  blood  of  the  left  than  of  the 
right  heart,  because  of  the  greater  dilution  of  the  venous  blood, 
owing  to  the  water  drawn  into  the  lungs  and  entering  the  pulmon- 
ary capillaries.  Exceptionally  this  difference  between  the  halves 
of  the  heart  is  not  apparent,  as  in  the  case  of  bodies  remaining 
submerged  for  a  long  period  and  in  those  in  which  the  circulation 
persists  for  a  few  moments  after  the  blood  dilution,  in  either  of 
which  instances  the  entire  blood  mass  tends  to  become  equally 
diluted.  The  utility  of  cryoscopy  as  a  forensic  test  of  death  by 
drowning  is  obvious  from  these  experiments,  although  its  value 
is  to  some  extent  restricted  by  the  fact  that  advanced  putrefaction 
and  prolonged  submersion  interfere  with  its  reliability. 

Cryoscopy  of  the  blood  and  urine  is  of  value  in  determining  . 
the  condition  of  renal  adequacy,  but  it  should  be  supplemented  by 
other  laboratory  tests  devised  for  this  purpose.  Forensically,  the 
test  may  yield  reliable  evidence  not  only  in  cases  of  death  by 
drowning,  but  possibly  also  in  the  identification  of  blood  stains 
from  various  sources. 

The  cryoscope  made  by  Fontaine,  of  Paris 
Fontaine's     (Fig.  35),  is  simply  constructed,  durable,  and 
Cryoscope.     thoroughly  satisfactory  for  clinical  use.    It  con- 
sists of  a  stout  glass  freezing -jar,  A,  provided  with 
a  large  test-tube,  B,  passing  to  its  center  and  kept  in  position  by  a 

1  Rif.  med.,  1901,  vol.  iii,  p.  109.  2  Amer.  Med.,  1902,  vol.  iii,  p.  656. 

3  For  an  excellent  resume  of  cryoscopy  in  all  its  phases  see  Cattell,  Proc.  Phila. 
Path.  Soc,  1904,  vol.  vi,  p.  244. 

4  Arch.  Ital.  de  Biol.,  1901,  vol.  xxxv,  p.  349. 

5  Munch,  med.  Wochenschr.,  1902,  vol.  xlix,  p.  1880. 


CRVOSCOPICAL  EXAMINATION. 


metal  support,  C.  At  the  base  of  the  jar  there  is  a  drain,  D,  for 
the  liquid  which  accumulates  as  the  ice-salt  mixture  melts.  A 
small  test-tube,  E,  having  a  lateral  vent,  F,  fits  within  the  larger 
tube,  being  adjusted  by  means  of  a  rubber  collar,  G,1  so  that  be- 
tween the  two  tubes  an  air  chamber  is  formed.  A  thermometer, 
H,  encircled  by  a  metal  spiral  stirrer,  I,  is  let  down  into  the 
smaller  test-tube  and  adjusted  so  that  it  touches  neither  the  walls 
nor  the  bottom  of  the  latter,  being  kept  in  this  position  by  means 
of  a  vertical  standard  fitted  with  an  adjustable  horizontal  arm. 
The  thermometer  registers  from  — 30  C.  to  +30  C,  being  gradu- 
ated in  2^-0'  of  a  degree,  and  is  provided  with  a  pear-shaped  bulb 
at  the  top,  to  allow  for  the  expansion  of 
the  mercury  column.  The  thermometer 
is  an  extremely  delicate  and  expensive 
bit  of  apparatus,  and  must  be  handled 
with  care,  for  fear  of  breakage.  It 
should  be  tested  with  distilled  water, 
so  that  any  deviation  may  be  taken  into 
account  in  subsequent  observations. 

Method  oj  Use  — The  freezing- jar, 
with  its  large  test-tube  adjusted,  is  filled 
to  the  brim  with  a  mixture  of  cracked 
ice  and  rock-salt,  packed  in  alternate 
layers,  the  whole  being  covered,  at  the 
level  of  the  mouth  of  the  jar,  with  a 
layer  of  salt  an  inch  in  depth.  The  size 
of  the  bits  of  ice  should  be  large  enough 
to  insure  gradual  thawing,  for  finely 
crushed  ice  rapidly  turns  to  slush.  Ten 
c.c.  of  the  blood  or  urine 2  are  placed  in 
the  small  test-tube,  which  is  laid  against 
a  block  of  ice,  to  cool,  while  the  freez- 
ing-jar is  being  packed.    By  the  time 

this  is  accomplished  (about  five  minutes)  the  fluid  to  be  tested 
will  have  cooled  sufficiently,  and  the  next  step  in  the  test  may 


Fig.  35. — Fontaine's  Cryoscope. 


1  In  the  original  model  of  the  instrument  this  collar,  as  well  as  the  metal  band 
supporting  the  large  test-tube,  interferes  with  the  reading  of  the  thermometer 
scale,  but  this  defect  may  be  easily  remedied  by  cutting  in  each  a  small  window, 
so  as  to  allow  a  clear  view  of  the  mercury  column.  The  apparatus  is  made  by 
G.  Fontaine,  16,  Rue  Monsieur  le  Prince,  Paris;  it  costs,  duty  free,  90  francs.  The 
A.  H.  Thomas  Company,  Philadelphia,  makes  an  excellent  cryoscope  of  the  Fon- 
taine model,  the  cost  of  which  is  considerably  less  than  that  of  the  French  instru- 
ment. 

2  The  patient's  blood  and  urine  should  be  collected  at  the  same  time:  the 
former  by  aspirating  a  superficial  vein,  the  latter  by  catheterizing  each  ureter  if 
the  test  involves  a  determination  of  the  integrity  of  each  kidney. 


106     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

proceed.    Great  care  must  be  taken  that  both  the  test-tubes 
and  the  thermometer  are  absolutely  dry,  for  the  slightest  trace 
of  moisture  so  alters  the  freezing-point  that  gross  inaccuracies 
in  the  final  reading  may  result.    The  small  test-tube  is  now 
fitted  within  the  larger  one,  after  which  the  thermometer,  with 
the  stirrer  in  place,  is  carefully  lowered  into  position,  rest- 
ing free  from  contact  with  the  walls  and  bottom  of  the  tube, 
with  its  mercury  bulb  immersed  in  the  test  fluid.    The  ther- 
mometer, when  correctly  adjusted,  is  hung  from  the  arm  of  the 
standard,  placed  alongside  the  freezing-jar.    The  handle  of  the 
stirrer  is  now  constantly  moved  up  and  down,  so  as  to  equalize  the 
temperature  of  the  test  fluid  as  it  congeals,  and  this  mixing  is  to  be 
continued  intermittently  during  the  rest  of  the  observation.  After 
a  wait  of  about  five  minutes  the  column  of  mercury  begins  to  fall, 
first  very  slowly,  then  rapidly,  to  approximately  two  degrees 
below  zero,  at  which  point  it  remains  for  a  few  moments,  and  then, 
because  of  the  heat  evolved,  rises  to  the  true  freezing-point,  where 
it  remains  stationary  for  about  two  minutes,  after  which  it  falls  to 
the  temperature  of  the  outside  mixture  of  ice  and  salt.    When  the 
point  of  stability  is  attained,  the  degree  registered  by  the  mercury 
column  is  noted  to  obtain  the  freezing-point  of  the  specimen.  In 
making  this  end-observation  the  eyes  should  be  on  a  level  with  the 
top  of  the  mercury  column.    It  may  be  hastened  somewhat  by  the 
insertion  of  a  pellet  of  ice  in  the  vent  of  the  small  test-tube  just 
before  the  freezing-point  is  reached. 

XL  ESTIMATION   OF   THE  RESISTANCE    OF  THE 
ERYTHROCYTES. 

This  method  of  examination  is  of  more  than  mere  theoretical 
value  in  the  study  of  diseases  associated  with  hemoglobinemia, 
in  which  conditions  it  indicates,  and  with  great  accuracy,  the  vul- 
nerability of  the  erythrocytes,  as  expressed  by  their  resistance  to  the 
action  of  salt  solutions  of  different  strengths.  Among  the  patho- 
logical conditions  in  which  the  method  is  useful  may  be  named  the 
severe  anemias,  the  specific  infections,  such  as  malarial  fever, 
yellow  fever,  and  sepsis,  all  forms  of  icterus,  the  different  cachectic 
states,  paroxysmal  hemoglobinemia,  and  toxemias  due  to  snake 
venom  and  to  other  hemolytic  agents. 

Hamburger's  method,  as  modified  by  von  Lim- 
Hamburger's  beck,1  requires  the  use  of  twelve  small  glass  recep- 
Method.      tacles,  about  the  size  of  a  Gowers'  hemocytometer 
mixing  cell,  each  of  which  contains  a  small  glass 

1  "Einer  klinische  Pathologie  des  Brutes,"  2d  ed.,  Jena,  1896;  also  New  Sy- 
denham Soc.  trans,  by  Arthur  Latham,  London,  1901. 


SPECTROSCOPICAL  EXAMINATION. 


bead.  Into  these  vessels  is  placed  i  c.c.  of  salt  solutions  of  dif- 
ferent strengths,  each  differing  by  0.02  per  cent.,  the  minimum 
being  0.3  per  cent.,  the  next  0.32  per  cent,  (or  0.02  per  cent, 
stronger),  and  so  on.  A  drop  of  blood  as  it  drips  from  the  puncture 
is  allowed  to  fall  into  each  of  the  vessels,  which  are  then  shaken 
briskly  for  a  minute  or  so,  in  order  to  cause  defibrination  by  the 
whipping  about  of  the  glass  beads.  When  this  is  accomplished, 
the  blood-charged  solutions  are  allowed  to  stand  for  six  hours, 
when  it  will  be  noted  that  some  of  them  are  tinged  with  hemoglobin, 
while  others  remain  clear.  The  first  tube  showing  no  solution  of 
hemoglobin  indicates  the  isotonicity  of  the  cells  under  examination. 
-  For  normal  blood  this  index  ranges  between  0.46  and  0.48  NaCl. 


XII.  SPECTROSCOPICAL  EXAMINATION. 
For  clinical  work  the  Sorby-Beck  microspectroscope,  to  be  used 
in  connection  with  the  microscope,  is  an  excellent  instrument, 
being  both  accurate  and,  comparatively 
speaking,  easy  to  manipulate.  Other 
very  perfect  instruments  for  the  spec- 
troscopical  examination  of  the  blood, 
differing  but  little  from  the  original 
Sorby  model,  are  also  made  by  Zeiss, 
by  Leitz,  and  by  Browning. 

This  instrument 
The         (Fig.  36)  when  in  use 

Sorby-Beck   fits  into  the  tube  of 

MiCROSPEC-  the  microscope  like  an 
troscope.  ordinary  ocular,  for 
which  it  is  substituted. 
Its  essential  part  consists  of  a  tube,  A , 
in  which  a  series  of  five  prisms,  two  of  Fig.  36. 
flint  and  three  of  crown  glass,  is  ar- 
ranged in  such  a  manner  that  the  emer- 
gent rays,  which  are  separated  by  dispersion,  leave  the  prisms  in 
practically  the  same  direction  as  that  taken  by  the  entering  im- 
mergent  ray.  At  one  side  of  the  tube  is  fixed  a  right-angle 
reflecting  prism,  so  that  the  spectrum  of  a  solution  of  normal 
blood  may  be  thrown  alongside  that  of  the  specimen  under 
investigation,  the  two  spectra  thus  being  comparable.  The  ad- 
justment of  the  spectra  is  effected  by  means  of  the  two  small 
screws,  B,  B' .  The  receptacle  containing  the  control  solution 
of  blood  is  clamped  to  the  stage,  C,  by  a  spring  clip,  D,  light  being 
reflected  through  the  liquid  and  into  the  rectangular  aperture,  E, 


Sorby-Beck  Microspec- 
troscope. 


Io8     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


by  the  swinging  mirror,  F.  The  width  of  this  aperture  is  controlled 
by  the  screw,  G.  The  receptacle  containing  the  blood  solution  to 
be  examined  is  placed  upon  the  stage  of  the  microscope,  being 
brought  into  focus  with  a  low-power  (f  or  i  inch)  dry  objective. 
Beneath  the  tube  inclosing  the  series  of  prisms  is  mounted  an 
achromatic  ocular,  below  which  a  narrow,  slit-like  diaphragm  is 
situated,  the  vertical  size  of  this  opening  being  regulated  by  a 
milled  screw,  not  shown  in  the  illustration,  and  its  breadth  by  the 
two  small  levers,  J,  /'.  Both  ocular  and  prisms  may  be  moved 
simultaneously  toward  and  away  from  the  diaphragm,  by  a  rack- 
and-pinion  mechanism  controlled  by  the  wheel,  /,  so  that  any  part 
of  the  spectrum  may  be  brought  into  focus. 

The  liquids  to  be  examined  should  be  placed  in  Sorby's  tubular 
cells,  and  cover-glasses  superimposed.  These  cells  (Fig.  37)  are 
narrow-lumened  glass  receptacles  made  of  barometer  tubing,  both 
ends  of  which  are  accurately  ground  to  parallel  surfaces,  one  end 
being  cemented  to  a  small  polished  glass  plate. 

Method  of  Examination.— The  specimen  of  blood,  obtained  in 
the  usual  manner,  by  puncture,  is  first  diluted 
fffj  with  distilled  water  100  times  by  means  of  the 

Thoma-Zeiss  erythrocytometer,  and  sufficient 
V  "      '  of  this  laked  blood  dropped  into  a  Sorby  cell 

FlG*  37lTrScelI  Tubu"  to  ^  ^  exactty  to  the  brim.  A  cover-glass  is 
then  carefully  laid  over  the  open  end  of  the 
cell,  the  precaution  being  taken  to  prevent  the 
formation  of  air-bubbles  upon  the  surface  of  the  column  of  liquid 
thus  inclosed.  A  second  cell,  to  be  used  as  the  control,  is  filled 
with  normal  blood,  similarly  diluted,  and  both  are  then  adjusted 
in  their  respective  positions,  as  already  explained. 

In  making  the  examination  a  ray  of  artificial  light  (that  from 
a  Welsbach  incandescent  burner  being  most  suitable)  is  projected 
by  the  microscope  mirror  through  the  lumen  of  the  cell  contain- 
ing the  suspected  blood,  and  the  surface  of  the  liquid  focused 
with  an  ordinary  ocular.  The  latter  is  then  removed  from  the 
microscope  tube  and  replaced  by  the  spectroscope  ocular,  and 
the  second  spectrum,  that  of  the  normal  blood,  is  brought  into 
proper  position  alongside  that  of  the  first,  so  that  any  differences 
between  the  two  may  be  contrasted  by  the  observer. 

The  appearance  of  the  spectra  of  normal  and  of  pathological 
blood,  together  with  the  circumstances  under  which  the  latter 
occur,  has  been  described  in  another  section.    (See  p.  168.) 


BACTERIOLOGICAL   EXAM  I  NATION. 


109 


XIII.  BACTERIOLOGICAL  EXAMINATION. 

The  demonstration  of  bacteria  in  the  circulating  blood,  pro- 
vided that  faultless  technic  is  employed,  furnishes  in  some  in- 
stances a  diagnostic  sign  of  the  greatest  importance.  The  patho- 
logical significance  of  such  a  finding  is  much  greater  than  that 
of  a  similar  result  obtained  postmortem,  since  with  the  latter 
there  is  no  means  of  determining  whether  the  bacterial  invasion 
of  the  blood  current  took  place  during  the  active  stages  of  the 
disease,  or  whether  it  occurred  as  either  a  preagonal  or  a  postag- 
onal  process. 

Cultural  methods  with  blood  aspirated  directly 
Methods,  from  a  superficial  vein  should  invariably  be  used 
whenever  such  a  procedure  is  practicable,  for 
blood  obtained  simply  by  pricking  the  skin  is  most  likely  to  be 
contaminated  with  various  bacteria  which  have  their  normal  hab- 
itat in  the  epidermis  and  its  appendages,  notably  by  the  Staphyl- 
ococcus epidermidis  alius.  Welch,1  who  first  drew  attention  to 
this  source  of  error,  emphasizes  the  fact  that  no  diagnostic  sig- 
nificance should  be  attached  to  the  demonstration  of  this  bac- 
terium in  blood  obtained  by  puncture  of  the  skin. 

Direct  examination  of  stained  cover-glass  specimens  prepared 
from  finger  blood  gives  either  negative  or  erroneous  results  in  the 
great  majority  of  instances.  In  certain  overwhelming  infections, 
notably  in  some  of  the  severer  forms  of  bubonic  plague,  it  may 
often  be  possible  to  detect  the  specific  micro-organism  in  the 
stained  film,  but  the  method  must  be  regarded  as  too  crude  and 
unreliable  to  furnish  accurate  findings  in  the  average  case. 

Blood  Cultures. — In  order  to  secure  the  most  reliable  informa- 
tion from  blood  culturing,  the  systematic  observance  of  three  pre- 
cautions is  essential.  First,  contamination  by  the  skin  bacteria 
above  referred  to  must  be  carefully  avoided,  by  the  thorough  ster- 
ilization of  the  patient's  skin  at  and  adjacent  to  the  site  from 
which  the  blood  is  aspirated.  Second,  not  less  than  0.5  c.c. 
of  blood  should  be  used  for  each  culture,  since  only  in  rare  in- 
stances are  bacteria  so  numerous  in  the  peripheral  circulation  as 
to  be  demonstrable  in  a  single  drop  of  blood.  Third,  fluid,  rather 
than  solid,  culture  media  should  be  used,  in  sufficiently  large 
quantities  to  dilute  the  blood  freely, — about  100  parts  of  me- 
dium to  each  part  of  blood,— the  object  of  this  precaution  being 
to  secure  attenuation  of  the  bactericidal  properties  of  the  blood, 
which  otherwise  might  prove  strong  enough  to  prevent  all  bac- 
terial development. 

tennis'  "System  of  Surgery,"  Philadelphia,  1895,  vol.  i,  p.  251. 


HO     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

For  aspirating  the  blood  the  author  prefers  to  use  a  tube  of 
about  10  c.c.  capacity,  like  that  illustrated  below  (Fig.  38). 
One  end  of  the  tube  is  ground  to  fit  a  No.  42  hypodermic 
needle,  while  over  the  other  end  (plugged  with  a  small  bit  of 
cotton)  is  slipped  a  piece  of  rubber  tubing  for  aspirating.  The 
apparatus,  minus  the  rubber  tubing,  is  inclosed  in  a  larger  glass 
tube,  both  open  ends  of  which  are  also  plugged  with  cotton,  and 
sterilized  by  dry  heat,  the  aspirating  tube  being  adjusted  at  the 
time  the  blood  is  to  be  collected.  This  instrument  is  far  superior 
to  an  antitoxin  or  a  hypodermic  syringe  for  the  purpose  intended, 
being  simple,  inexpensive,  easily  sterilized,  and  readily  cleaned 
after  use.  It  is  especially  well  adapted  for  making  cultures  at  a 
distance  from  a  laboratory,  where  the  sterilization  of  an  ordinary 
piston-syringe  is  difficult,  if  not  impossible. 

At  least  one  hour  before  the  aspiration  of  the  blood  the  skin 
of  the  patient's  arm  at  and  for  some  distance  on  all  sides  of  the 
bend  of  the  elbow  should  be  scrubbed  thoroughly  for  several 


Fig.  38— Aspirating  Tube  for  Blood  Culturing. 


minutes  either  with  a  strong  ethereal  soap  or  with  tincture  of 
green  soap,  after  which  the  part  is  well  rinsed  with  hot  sterile 
water,  and  finally  washed  with  alcohol  and  ether.  A  moist  hot 
1 : 500  bichlorid  compress  is  then  applied  over  the  site  thus  cleaned, 
being  left  in  place  until  the  time  of  the  withdrawal  of  the  blood. 
As  a  preliminary  to  this  operation  the  dressing  is  removed,  and 
the  part  freely  douched  and  scrubbed  with  hot  sterile  water,  in 
order  to  remove  every  trace  of  the  bichlorid.  A  rubber  drain- 
age tube,  previously  sterilized,  is  twisted  tightly  around  the  pa- 
tient's arm  above  the  bend  of  the  elbow,  so  as  to  cause  disten- 
tion of  the  superficial  veins  in  this  situation,  and  the  point  of  the 
needle  is  then  thrust  obliquely  into  the  most  prominent  of  these 
vessels,  with  the  result  that  the  blood  immediately  begins  to  flow 
into  the  bore  of  the  instrument.  If,  for  any  reason,  the  force  of 
the  blood  flow  should  fail  to  fill  the  caliber  of  the  tube,  sufficient 
blood  may  easily  be  obtained  by  making  gentle  suction  through 
the  rubber  tubing.  While  introducing  the  needle  it  should  be  held 
almost  parallel  to  the  long  axis  of  the  vein,  for  should  it  be  simply 


B  ACT  KRIOLOC.ICAL   F.  X  A  M  1  N  AT  ION. 


Ill 


plunged  into  the  vessel  at  right  angles,  there  is  danger  that  the 
point  will  pass  completely  through  the  vessel  from  wall  to  wall 
and  penetrate  the  surrounding  tissues — an  accident  which  may 
explain  the  cause  of  many  a  "dry  tap."  The  site  of  the  aspira- 
tion may  be  made  anesthetic  by  preliminary  freezing  with  a  spray 
of  ethyl  chlorid,  but  to  most  patients  the  operation  is  not  painful 
enough  to  necessitate  this. 

Having  thus  collected,  say,  10  c.c.  of  blood,  the  con- 
tents of  the  tube  are  divided  equally  among  five  Pasteur  flasks, 
each  containing  at  least  200  c.c.  of  broth  or  other  suitable 
fluid  culture  medium.  The  flasks  are  then  shaken  for  a  few 
moments,  in  order  to  mix  the  blood  and  medium  and  to  dilute 
thoroughly  the  former,  after  which  they  are  placed  in  an  in- 
cubator. The  identity  of  the  growths,  should  any  occur,  remains 
to  be  determined  by  secondary  culturing  and  microscopical  ex- 
amination, for  descriptions  of  which  the  student  should  consult 
text-books  on  bacteriology.  Cultures  made  by  this  technic, 
suggested  by  Adami,1  are  much  more  favorable  to  the  growth 
of  any  bacteria  which  may  be  in  the  blood  stream  than  the  older 
methods  of  using  solid  media,  except  under  special  circumstances, 
such  as  the  cultivation  of  the  gonococcus,  the  influenza  bacillus,  and 
other  germs  which  grow  most  luxuriantly  on  special  forms  of 
media. 

Staining  Methods.-— In  the  limited  number  of  instances  to  which 
such  methods  are  applicable  the  technic  described  below  will  be 
found  useful. 

An  attempt  should  be  made  to  sterilize  the  skin  of  the  finger 
from  which  the  blood  is  obtained  by  thoroughly  scrubbing  the 
part  first  with  ethereal  or  green  soap,  and  then  with  a  1 : 500 
bichlorid  solution,  alcohol,  and  ether,  in  the  order  named,  this 
being  followed  by  sponging  with  sterile  water.  A  deep  punc- 
ture having  been  made  with  a  needle  which  has  been  sterilized 
by  the  naked  flame,  and  the  first  few  drops  of  blood  escaping 
from  the  wound  allowed  to  drip  away,  one  of  the  succeeding 
drops  is  transferred  by  means  of  a  sterile  platinum  needle  to  the 
surface  of  a  cover-glass  upon  which  a  second  cover-glass  is  at 
once  laid,  the  two  being  drawn  apart,  in  order  to  secure  a  pair 
of  spreads.  The  latter  are  immediately  dried  by  gentle  heat 
and  then  passed  several  times  through  a  Bunsen  flame.  It  is 
needless  to  add  that  the  cover-glasses  used  for  making  the  films 
must  be  sterilized  by  heat,  and  handled  by  means  of  a  pair  of 
sterile  forceps.  Films  thus  prepared  may  be  stained  with  any  of 
the  basic  anilin  dyes  (thionin,  methylene-blue,  and  methyl-  or 

1  Jour.  Amer.  Med.  Assoc.,  1899,  vol.  xxxiii,  p.  15 14. 


112     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

gentian- violet  being  most  useful  for  this  purpose),  after  which 
they  are  washed  in  water,  dried,  and  mounted  in  Canada  balsam 
or  in  cedar  oil.  Should  a  double-stained  specimen  be  desired, 
one  of  the  eosin  and  methylene-blue  solutions  referred  to  previously 
may  be  depended  upon  to  give  satisfactory  results. 

Giinther's  method1  will  be  found  useful  if  the  object  is  to  de- 
stroy the  color  of  the  erythrocytes,  so  as  to  leave  a  freer  field  of 
vision  for  any  bacteria  which  may  be  present  in  the  film.  Ac- 
cording to  this  method,  the  specimen  is  first  immersed  for  ten 
seconds  in  a  5  per  cent,  aqueous  solution  of  acetic  acid,  until 
the  tint  of  the  hemoglobin  has  entirely  faded  away,  after  which 
the  reagent  is  removed  by  briskly  blowing  upon  the  surface  of 
the  cover-glass;  the  latter  is  then  held,  face  downward,  over  the 
open  mouth  of  a  tyottle  containing  strong  ammonia  water,  so  as 
to  neutralize  all  remaining  traces  of  the  acid.  The  film  is  now 
stained  for  twenty-four  hours  with  the  Ehrlich-Weigert  fluid 
(contained  in  a  covered  staining  dish),  at  the  end  of  which  time 
it  will  be  found  to  be  colored  a  deep  blue.  It  is  then  decolorized 
by  a  few  seconds'  immersion  in  a  1  114  aqueous  solution  of  nitric 
acid,  until  the  color  fades  to  a  light  green;  rinsed  in  alcohol;  dried 
in  air;  and  mounted  in  balsam. 

The  Ehrlich-Weigert  fluid  is  prepared  by  adding  from  10  to 
15  drops  of  anilin  oil  to  6  ex.  of  distilled  water,  held  in  a  test- 
tube.  The  fluid  is  thoroughly  mixed  by  shaking,  and  then  filtered. 
To  the  filtrate  a  few  drops  of  a  concentrated  alcoholic  solution 
of  methyl-  or  gentian-violet  are  added — just  sufficient  of  the  dye 
to  produce  a  slight  turbidity  of  the  liquid,  which  clears  up  in  a 
few  minutes.  The  mixture  prepared  in  this  manner  is  employed 
as  the  staining  agent. 


XIV.    DETERMINATION  OF  THE  SERUM  REACTION. 

In  1894  Pfeiffer2  noticed  that  the  vibrios  of 
Widal's      Asiatic  cholera,  if  injected  into  the  peritoneal 
Test.        cavity  of  a  guinea-pig  immunized  against  this 
disease,  rapidly  lost  their  characteristic  motility, 
and  tended  to  become  granular,  broken  up,  and  dissolved,  while 
in  the  healthy,  non-immune  animal 'they  developed  normally  and 
abundantly,  and  failed  to  show  any  such  changes  in  their  mor- 
phology.   He  claimed  that  this  reaction,  known  as  "Pfeiffer's 

1  Fortsehr.  d.  Med.,  1885,  vol.  iii,  p.  775. 

2Zeitschr.  f.  Hyg.,  1894,  vol.  xviii,  p.  1;  ibid.,  1895,  vol.  xix,  p.  75;  also 
Centralbl.  f.  Bakt.  u.  Parasitenk.,  1896,  vol.  xix,  p.  191;  also  Deutsch.  med. 
Wochenschr.,  1896,  vol.  xxii,  p.  97. 


DETERMINATION  OF  THE  SERUM  REACTION.  II3 

phenomenon,"  was  specific,  and  emphasized  its  value  as  a  means 
of  laboratory  differentiation.  Two  years  later  Pfeiffer  and  Kolle1 
found  that  the  same  changes  occurred  in  experiments  with  the 
bacillus  of  Eberth  and  animals  rendered  immune  to  enteric  fever, 
and,  furthermore,  discovered  that  the  test  could  be  conducted  in 
vitro,  by  mixing  in  a  test-tube  typhoid  cultures  and  immune  serum. 
It  is  of  interest  to  note  that  results  somewhat  analogous  to  those  of 
Pfeiffer  had  been  observed  in  1891  by  Metschnikoff,2  and  in  1889 
by  Bordet,3  and  by  Charrin  and  Roger,4  although  none  of  these 
workers  appeared  to  recognize  the  significance  of  their  observa- 
tions. 

In  1896  Griiber  and  Durham5  applied  the  principles  of  Pfeif- 
fer's  phenomenon  to  many  other  motile  as  well  as  non-motile 
bacteria,  deduced  new  facts  regarding  its  utility  as  a  means  of 
differentiating  various  species  of  germs,  improved  the  technic 
of  the  test,  and  made  the  important  announcement  that  aggluti- 
nation and  immobility  of  typhoid  bacillus  cultures  were  pro- 
duced by  the  action  of  blood  serum  from  a  patient  having  re- 
cently recovered  from  an  attack  of  enteric  fever.  It  remained, 
however,  for  Widal,6  in  1896,  first  to  apply  the  reaction  clinically, 
and  to  announce  that  enteric  fever  could  be  diagnosed  by  noting 
the  clumping  and  immobilization  of  the  typhoid  bacillus  when 
mixed  in  definite  proportions  with  blood  serum  from  a  patient 
suffering  from  typhoid.  This  reaction,  Widal  insisted,  was  one  of 
infection,  and  was  demonstrable  not  only  during  convalescence, 
but  during  the  incipiency  and  the  height  of  the  disease. 

The  serum  reaction  is  to-day  recognized  as  an  important  sign 
in  the  diagnosis  not  only  of  enteric  fever,  but  also  of  Asiatic 
cholera,  Malta  fever,  relapsing  fever,  paracolon  infections,  and 
bacillary  dysentery,  while  its  value  still  remains  less  certainly 
established  in  many  other  conditions,  such  as,  for  example,  lep- 
rosy, tuberculosis,  bubonic  plague,  sepsis,  and  pneumococcus  in- 
fections. The  technic  of  the  test  and  its  diagnostic  significance 
under  various  circumstances  will  be  described  under  the  headings 
of  the  diseases  in  which  it  occurs.  (See  Section  VII,  "  General 
Hematology.") 

1  Zeitschr.  f.  Hyg.,  1896,  vol.  xxi,  p.  203;  also  Deutsch.  med.  Wochenschr.,  1896, 
vol.xxii,p.  735. 

2  Annal.  de  PInstitut  Pasteur,  1891,  vol.  v,  p.  473;  ibid.,  1894,  vol.  viii,  p.  714; 
ibid.,  1895,  vol.  ix,  p.  433. 

3  Ibid.,  1895,  vol.  ix,  p.  462;  ibid.,  1896,  vol.  x,  p.  191 . 

4  Compt.  rend.  Soc.  biol.,  Paris,  1889,  vol.  i,  p.  667. 

5  Munch,  med.  Wochenschr.,  1896,  vol.  xliii,  p.  285. 

6  Bull,  med.,  1896,  vol.  x,  pp.  618  and  766;  Sem.  med.,  1896,  vol.  xvi, 
p.  259;  ibid.,  1897,  vol.  xvii,  p.  69;  Lancet,  1896,  vol.  ii,  p.  1371;  Munch, 
med.  Wochenschr.,  1897,  vol.  xliv,  p.  202. 

8 


114     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

XV.  MEDICO-LEGAL  TESTS  FOR  BLOOD. 

The  examination  of  suspected  blood  stains  for  forensic  pur- 
poses includes  microscopical  search  for  blood  corpuscles,  spec- 
troscopy, the  hemin  and  guaiacum  tests,  and  the  biological  serum 
test  of  Bordet.  The  first  three  of  these  procedures  are  used 
merely  to  determine  whether  a  given  stain  is  or  is  not  composed 
of  blood,  but  they  failed  conclusively  to  prove  the  source  of  the 
latter.  By  the  biological  reaction  it  is  possible  to  supplement 
these  tests  by  proving  the  precise  origin  of  the  blood,  whether 
human  or  derived  from  one  of  the  lower  animals.  It  need  scarcely 
be  added  that  in  medico-legal  work  it  is  essential  to  use  all  four 
tests  in  the  investigation  of  the  material  submitted  for  study. 

In  undertaking  the  demonstration  of  eryth- 
Microscopical  rocytes  in  a  dried  clot,  the  latter  must  be 
Examination,  treated  with  an  agent  which  will  macerate  and 
dissolve  the  cells  without  laking  them  and 
thus  removing  their  hemoglobin  and  altering  their  shape.  Vir- 
chow's  fluid — a  30  per  cent,  aqueous  solution  of  potassium  hydrate 
— is  suitable  for  this  purpose;  or  Ranvier's  solution — a  saturated 
aqueous  solution  of  iodin  containing  2  per  cent,  of  potassium  iodid 
— may  be  used ;  this  stains  various  starchy  cells  which  might  other- 
wise counterfeit  blood  cells.  The  solution  having  been  effected, 
a  minute  portion  of  the  dissolved  stain  is  either  mounted  as  a  wet 
specimen  or  spread  as  a  dry  film  between  cover-glasses,  subse- 
quently stained  with  appropriate  dyes,  and  mounted  in  balsam 
as  a  permanent  specimen.  For  the  microscopical  examination 
a  yy-inch  oil-immersion  objective'is  essential,  and,  if  measurements 
are  to  be  attempted,  an  ocular  micrometer. 

If  corpuscles  resembling  those  of  blood  are  detected  in  the 
specimen,  especial  attention  should  be  directed  to  their  average 
size,  their  shape,  and  to  the  presence  or  absence  of  nuclei.  The 
diameter  of  the  normal  human  erythrocyte  (-32V0  in.)  is  almost 
equaled  by  that  of  the  dog's  corpuscles,  which  averages  approxi- 
mately -3-5-V0  m-  ^  tne  ce^s  are  disc-shaped  and  measure  yoVo" 
in.  or  less  in  diameter,  it  is  safe  to  consider  them  non-human, 
and  belonging  to  some  one  of  the  common  domestic  animals, 
such  as  the  cat,  horse,  cow,  ox,  pig,  sheep,  or  goat.  If  the  cor- 
puscles are  of  oval  shape  and  nucleated,  they  are  certainly  not 
mammalian,  but  are  derived  from  a  fowl,  a  fish,  or  a  reptile.  A 
possible,  though  highly  improbable,  contradiction  to  these  general 
premises  must  be  recalled,  namely,  the  structural  alterations  of 
human  erythrocytes  occurring  in  anemic  bloods — particularly 
the  tendency  toward  microcytosis  in  chlorosis,  and  toward  megalo- 


MEDICO-LEGAL  TESTS  FOR  BLOOD. 


cytosis,  poikilocytosis  (often  of  oval  character),  and  nucleation  in 
intense  anemia,  such  as  that  of  the  primary  pernicious  type. 
Leukemic  blood,  however,  is  characteristically  hall-marked.  Here 
may  be  noted  Dresbach's  case,1  unique  of  its  kind,  of  a  healthy 
young  mulatto  90  per  cent,  of  whose  erythrocytes  were  of  oval 
or  elliptical  shape. 

In  a  considerable  proportion  of  cases  microscopical  examina- 
tion of  a  dried  blood  clot  avails  nothing,  owing  to  the  destructive 
changes  which  have  taken  place  in  the  cells.  Even  under  the 
most  favorable  conditions  all  one  can  usually  accomplish  with  the 
aid  of  microscopy  is  to  hazard  an  opinion  that  a  given  specimen 
of  blood  is  either  mammalian  or  derived  from  a  fowl,  a  fish,  or  a 
reptile.  For  the  medico-legal  aspects  of  such  examinations, 
together  with  the  rigid  technical  precautions  demanded,  the 
reader  is  referred  to  the  standard  works  on  forensic  medicine.2 

This  method  of  examination  has  already  been 

Spectros-  described.  (See  p.  107.)  It  is  to  be  employed 
copy.  whenever  ,a  sufficient  quantity  of  a  blood  solu- 
tion is  available,  the  purpose  being  to  deter- 
mine the  presence  or  absence  of  blood  pigment,  and  further  to 
identify  its  particular  variety.  If  the  blood  clot  is  tolerably  fresh, 
it  may  yield,  in  aqueous  solution,  the  absorption  bands  of  oxy- 
hemoglobin, which,  on  the  addition  of  ammonium  sulphid,  charac- 
teristically change  to  the  spectrum  of  reduced  hemoglobin.  Old 
stains,  especially  those  whose  hemoglobin  has  been  altered  by 
exposure  to  the  air  and  sunlight,  show  a  spectrum  of  methemo- 
globin,  while  blood  which  has  undergone  putrefaction,  in  addition 
to  yielding  this  spectrum,  shows  that  of  hematin.  Recent  stains 
can  usually  be  dissolved  in  distilled  water,  but  old  clots  require 
a  more  active  solvent,  such  as  acetic  acid  or  sodium  hydroxid. 
When  such  reagents  are  used,  the  spectra  either  of  acid  hematin 
or  of  alkaline  hematin  result,  according  to  the  reaction  of  the 
solvent  employed.  If  the  stain  has  been  subjected  to  a  high  de- 
gree of  heat,  with  the  consequent  formation  of  hematoporphyrin, 
it  should  be  dissolved  with  concentrated  sulphuric  acid,  the  re- 
sulting solution  producing  the  spectrum  of  hematoporphyrin  in 
acid  solution. 

If  positive,  Teichmann's  hemin  test  is  certain 
Teichmann's   proof  of  blood,  although  it  does  not,  of  course, 
Hemin  Test,   indicate  its  source.    The  test  is  of  extreme  deli- 
cacy, and  may  be  relied  upon  to  show  the 
presence  of  the  slightest  trace  of  blood  in  the  material  examined, 

1  Jour.  Amer.  Med.  Assoc.,  1904,  vol.  xlii,  p.  837. 

2  Peterson  and  Haines,  "Text-book  of  Legal  Medicine  and  Toxicology," 
Philadelphia,  1904;  Tidy,  "Legal  Medicine,"  London,  1882. 


Il6     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


provided  that  the  composition  of  the  blood  is  not  too  materially 
altered.  Negative  results  are  therefore  not  conclusive,  since  the 
reaction  may  fail  in  stains  exposed  to  a  high  temperature  or  to  the 
prolonged  action  of  the  sun's  rays,  and  in  those  contaminated  by 
certain  substances,  such  as  naphtha,  iron  rust,  lime,  lead,  and 
animal  charcoal. 

The  hemin  test  is  carried  out  as  follows  :  A  small  particle 
of  the  suspected  material,  reduced  to  a  fine  powder,  is  mixed  with  a 
drop  of  normal  salt  solution  upon  the  surface  of  a  glass  slide,  the 
mixture  then  being  evaporated  slowly  by  moderate  heat  until  a 
dry  film  forms.  Care  should  be  observed  not  to  use  too  great  heat 
in  the  evaporation,  for  fear  of  spoiling  the  reaction  by  causing 
decomposition  of  the  hematin.  The  dry  film  is  now  covered  with 
a  cover-glass,  under  which  a  drop  of  glacial  acetic  acid  is  allowed 
to  flow,  after  which  the  slide  is  again  heated  until  minute  bubbles 
begin  to  form.  At  this  instant  the  heating  should  cease,  and  the 
preparation  be  allowed  to  cool.  Active  boiling  at  this  stage  of 
the  test  may  drive  off  all  the  free  hydrochloric  acid  evolved  by  the 
addition  of  acetic  acid,  and  thus  prevent  the  formation  of  the 
sought-for  crystals.  When  cool,  the  specimen  is  examined  micro- 
scopically with  a  low  power  inch)  dry  objective,  which  shows, 
if  the  material  contained  blood,  distinctive  crystals  of  hemin  or 
hematin  hydrochlorid,  consisting  of  yellow  or  brown  rhombo- 
hedral  plates,  lying  singly  and  arranged  as  crosses  or  as  stellate 
designs. 

Van  Deen's  guaiacum  test  is  sufficiently  deli- 
The  Guaiacum  cate  to  show  the  presence  of  blood  pigment  in 
Test.  a  solution  as  dilute  as  i  :  5000,  but  unfortunately 
it  responds  to  so  many  other  substances  that  its 
only  value  is  as  a  negative  sign.  A  bit  of  the  suspected  clot  or  a 
shred  of  the  stained  fabric  is  moistened  with  distilled  water,  in 
order  to  dissolve  the  blood  pigment,  and  to  this  solution  are  added 
a  few  drops  of  freshly  prepared  tincture  of  guaiacum.  To  this  a 
drop  or  two  of  hydrogen  peroxid  is  added,  with  the  result  that  a 
blue  color  immediately  develops  in  the  presence  of  even  minute 
traces  of  blood.  Or  the  test  may  be  carried  out  just  as  satis- 
factorily simply  by  pressing  against  the  dry  stain  a  piece  of  wet 
filter-paper,  and  then  adding  to  the  moist  daub  thus  made  the 
guaiacum  and  peroxid.  According  to  Peterson  and  Haines,1  the 
following  substances  produce  the  same  reaction  with  this  test  as 
given  by  blood  pigment :  potato  skin,  casein,  glue,  iron  and  copper 
compounds,  the  double  chlorid  of  gold  and  sodium,  manganese 
dioxid,  potassium  permanganate,  and  indigo;  all  of  which  means 

1  Loc.  cit. 


MKDICO  LKG  VL  TKSTS   I'OR  BLOOD. 


117 


that  a  positive  reaction  indicates  absolutely  nothing  definite, 
although,  on  the  other  hand,  a  negative  result  proves  with  great 
certainty  the  absence  of  blood  pigment  in  the  material  examined. 

Originally  Bordet,1  later  Uhlenhuth  and 
The  Biolog-  Tchistovitch,2  Wassermann  and  Schutze,3  and 
ical  Test  others  demonstrated  the  important  fact  that  the 
for  Blood,  blood  serum  of  an  animal  into  which  has  been 
injected  the  blood  of  another  animal  of  different 
species  develops  the  property  of  agglutinating  and  dissolving 
erythrocytes  similar  to  those  injected,  but  has  no  such  effect  upon 
blood  derived  from  another  source.  The  principle  of  this  biologi- 
cal reaction  is  well  expressed  by  Valee's  law:  If  an  animal,  A,  be 
inoculated  repeatedly  with  an  albuminoid  material  from  an  animal 
of  a  different  species,  B,  the  blood  serum  of  A  acquires  the  specific 
property  of  precipitating  in  vitro  albuminoid  fluids  derived  from 
animals  belonging  to  the  species  B.  Thus,  in  the  blood  of  the 
inoculated  animal  are  developed  antibodies  selectively  hostile  to 
the  toxic  principles  of  substances  identical  with  those  injected, 
and  the  serum  containing  such  antibodies  is  known  as  an  anti- 
serum. Lysins,  which  dissolve ;  precipitins,  which  precipitate ;  and 
agglutinins,  which  clump,  the  poisonous  substances  and  antidote 
their  toxicity,  are  examples  of  the  antibodies  evolved  in  this 
manner.  On  this  principle  it  is  possible  to  produce  antisera  not 
only  for  homologous  bloods,  but  also  for  different  animal  albumin- 
ous fluids  and  cells  and  for  vegetable  albumins.  For  instance, 
such  sera  have  been  developed  which  react  specifically  with  cow's 
milk,  with  horse-meat,  with  semen,  with  various  epithelial  cells, 
and  with  a  number  of  other  substances  homologous  to  those 
injected. 

In  the  case  of  antisera  for  various  bloods,  while  the  test  is 
specific  with  homologous  blood,  it  is  also  true  that  feeble  reactions 
may  occur  with  the  blood  of  closely  related  species.  Thus, 
rabbits  treated  with  human  blood  yield  a  serum  reacting  not 
only  with  the  blood  of  man,  but  also  with  that  of  certain  species 
of  monkeys.  Nuttall  and  Dinkelspiel4  and  Grunbaum5  showed 
that  it  is  the  blood  of  the  anthropoid  apes  (Simiadce),  especially 
the  gorilla,  the  chimpanzee,  and  the  orang,  which  reacts  most 

1  Annal.  de  l'lnstitut  Pasteur,  1898,  vol.  xii,  p.  688;  ibid,  1899,  vol.  xiii, 
P-  273- 

Deutsch.  med.  Wochenschr.,  1901,  vol.  xxvii,  p.  82;  ibid.,  1902,  vol.  xxviii, 
pp.  659  and  679. 

3  Berlin,  klin.  Wochenschr.,  1901,  vol.  xxxviii,  p.  187;  also  Wassermann, 
"Immune  Sera  "  (Eng.  trans,  by  Chas.  Bolduan),  New  York,  1904. 

4  Brit.  Med.  Jour.,  1901,  vol.  i,  p.  1141;  also  Nuttall,  "Blood  Immunity  and 
Blood  Relationship,"  Cambridge,  1904. 

5  Lancet,  1902,  vol.  i,  p.  143. 


Il8     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

decidedly  with  human  antiserum;  while  the  lower  orders  of 
monkeys,  represented  by  the  Hapalidce,  the  Cercopithecidcz,  and 
the  Cebidce,  give  less  positive  results.  Practically,  this  startling 
biological  confirmation  of  Darwin's  views  is  scarcely  a  source  of 
error,  since  in  high  dilutions  (500  or  more)  human  antiserum  does 
not  show  a  precipitate  even  with  the  highest  order  of  primates' 
blood  (Layton1). 

Antisera  for  horses,  cattle,  sheep,  pigs,  dogs,  birds,  and  other 
animals  and  fowls  all  react  typically  with  homologous  bloods, 
but  also  sometimes,  although  always  atypically,  with  alien  bloods. 
Pig  antiserum,  for  example,  reacts  faintly  with  the  blood  of  the 
wild  boar;  horse  antiserum  with  donkeys'  blood;  fox  antiserum 
with  wolves'  and  dogs'  blood;  and  sheep  antiserum  with  goats' 
blood.  It  is  a  notable  fact  that  these  are  reactions  between 
biologically  related  species  of  animals,  and  that  they  are  feeble 
and  atypical,  in  comparison  with  the  reactions  occurring  between 
homologous  antisera  and  bloods.  It  is  also  true  that  the  more 
remote  the  biological  relation  of  the  animal  from  the  one  whose 
blood  activates  the  antiserum,  the  feebler  the  reaction  becomes. 
As  explained  subsequently,  these  pseudo-reactions  do  not  occur 
if  the  blood  to  be  tested  is  adequately  diluted  before  examination. 

Technic. — Preparation  of  the  Antiserum. — The  antiserum  is 
prepared  by  injecting  healthy  rabbits  with  from  5  to  10  c.c.  of 
human  defibrinated  blood,  at  intervals  of  about  four  days,  until  a 
total  of  between  50  and  80  c.c  has  been  administered.  One  or 
two  weeks  after  the  last  injection  the  animal  is  bled,  and  the  serum 
obtained  is  collected  in  sterile  test-tubes,  which  are  sealed  and 
stored  for  future  use.  Belgian  hares  are  excellent  antiserum 
producers,  and  are  preferable  to  ordinary  rabbits,  being  more 
resistant  to  the  toxic  effects  of  the  injections,  and  yielding  highly 
potent  antiserum.  Goats,  sheep,  and  dogs  have  also  been  used, 
but  not  with  wholly  satisfactory  results.  Ewing2  obtained  ex- 
cellent antiserum  from  a  hen,  which,  being  biologically  far  re- 
moved from  man,  should  theoretically  furnish  a  highly  selective 
human  antiserum. 

The  blood  used  for  the  immunization  may  be  conveniently 
secured  from  the  placenta  and  umbilical  cord.  It  is  collected  in  a 
sterile  flask  containing  several  small  glass  beads,  which  defibrinate 
the  blood  when  the  flask  is  agitated  for  a  few  minutes.  The  blood 
thus  defibrinated  may  be  injected  immediately  into  the  animal, 
or  placed  in  a  refrigerator  for  subsequent  use.  The  fresher  the 
blood  injected,  however,  the  more  powerful  the  antiserum  which  it 
produces.    The  injections  may  be  subcutaneous,  intravenous,  or 

1  Amer.  Med.,  1903,  vol.  v,  p.  913.         2  Med.  News,  1903,  vol.  lxxxiii,  p.  925. 


MEDICO-LEGAL  TESTS  FOR  BLOOD. 


II9 


intraperitoneal,  the  last  being  the  simplest  and' least  dangerous 
to  the  animal  if  properly  carried  out.  One-half  of  the  rabbit's 
lower  abdomen  having  been  shaved  and  disinfected  with  a  sub- 
limate solution,  the  needle  of  the  syringe  is  firmly  thrust  through 
the  tissues  at  a  point  within  the  prepared  area,  and  the  injection 
made  when  the  abdominal  cavity  is  entered.  Experience  will 
determine  the  amount  of  pressure  and  manipulation  necessary  to 
penetrate  the  abdomen  to  a  sufficient  depth  and  to  avoid  wounding 
the  gut.  While  making  the  injection  an  assistant  should  hold  the 
animal  in  such  a  position  that  its  abdominal  wall  is  kept  tense. 
Since  the  injection  of  human  blood  not  infrequently  causes  toxic 
symptoms  in  the  treated  animals,  they  should  be  kept  in  the  best 
possible  hygienic  surroundings,  with  ample  runways,  an  abundance 
of  air  and  light,  and  plenty  of  food  and  water.  _  It  is  a  good  plan 
temporarily  to  discontinue  the  injections  in  animals  which  show 
marked  loss  of  weight  and  other  evidences  of  severe  reaction. 

The  blood  of  the  animal  under  treatment  should  be  tested 
from  time  to  time,  and  when  found  to  be  sufficiently  potent  with 
human  blood,  the  injections  are  stopped.  A  week  or  two  later  the 
antiserum  will  be  sufficiently  powerful,  and  it  is  then  collected  by 
bleeding  the  rabbit  either  from  an  ear  vein  or  from  the  carotid 
artery.  In  neither  instance  is  it  necessary  to  exsanguinate  the 
animal.  The  blood  is  collected,  under  aseptic  precautions,  in 
a  dish,  from  which  the  serum,  after  coagulation  has  occurred, 
is  pipetted  into  small  sterile  test-tubes  measuring  10  cm.  in 
height  by  0.5  cm.  in  diameter.  The  rilled  tubes  are  then 
plugged  with  cotton  and  set  upright  in  a  refrigerator  until  re- 
quired for  the  test.  As  a  preservative  a  few  drops  of  chloroform 
may  be  added  to  each  tubeful  of  antiserum.  If  this  is  done, 
however,  the  antiserum  must  be  incubated  for  half  an  hour  before 
being  used,  in  order  to  remove,  by  volatilization,  all  traces  of  the 
chloroform,  which  otherwise  might  cause  a  pseudo-reaction  with 
alien  blood.  Other  preservatives,  such  as  lysol,  lysoform,  carbolic 
acid,  and  thymol,  may  also  cause  clouding  of  antiserum,  and 
therefore  should  not  be  used.  Solutions  of  mercuric  chlorid 
strong  enough  to  be  antiseptic  destroy  the  antiserum. 

The  test  antiserum  may  be  preserved  in  dry  form  by  pouring 
it  into  Petri  dishes  and  drying  in  a  cool  place,  the  film  thus  ob- 
tained being  powdered  and  kept  in  a  tightly  stoppered  bottle  until 
required  for  use.  To  prepare  the  antiserum,  this  powder  is  simply 
dissolved  in  normal  salt  solution  in  definite  proportions. 

Testing  the  Suspected  Stain. — In  all  cases  the  suspected  stain 
must  be  proved  to  be  blood  by  the  hemin  crystal  test,  the  spectro- 
scope, and  the  other  older  methods  described  above.    This  is 


120     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 

highly  essential  in  forensic  work,  because  body  albumins  other  than 
blood  (sputum,  saliva,  pus,  feces,  exudates,  and  albuminous  urine) 
are  capable  of  giving  positive  reactions  with  human  antiserum. 
Contamination  by  such  materials  is,  however,  readily  detectable 
by  other  tests. 

The  stain  to  be  examined  is  dissolved  with  a  few  drops  of  a  0.6 
per  cent,  aqueous  solution  of  chemically  pure  sodium  chlorid,1  and 
the  resulting  cloudy  mixture  cleared  by  filtration  through  either 
asbestos  or  Schleicher's  "blue  ribbon"  filter-paper,  or  by  centrif- 
ugalization.  The  solution  of  the  stain  thus  rendered  perfectly 
clear  is  then  added  to  the  antiserum  in  the  proportion  of  at  least 
100  to  1,  and  the  mixture  incubated  at  370  C.  If  the  test  be  posi- 
tive,^ distinctly  flocculent  precipitate  will  form  in  the  test-tube 
within  three  hours,  this  reaction  being  preceded  by  the  formation 
of  a  more  or  less  marked  turbidity  immediately  or  very  shortly 
after  having  mixed  the  antiserum  and  the  blood  solution.  Slight 
turbidities  do  not  constitute  positive  reactions— they  may  occur 
with  heterologous  bloods  in  dilutions  less  than  the  above.  Several 
controls  are  also  to  be  prepared  and  incubated  simultaneously: 
one  of  the  salt  solution  used  as  a  solvent;  a  second  of  the  pure 
dissolved  and  cleared  stain;  a  third  of  the  pure  test  antiserum; 
a  fourth  of  human  blood  and  normal  rabbit's  serum;  and  a  fifth 
of  human  blood  and  the  test  antiserum.  All  but  the  last  of  these 
controls  should  remain  clear. 

Sources  of  Error.— Aside  from  pseudo-reactions  due  to  under- 
dilution  of  the  antiserum,  accidental  clouding  and  precipitation 
may  arise  from  the  following  group  of  factors: 

1.  Bacterial  Growths.— Antiserum  clouded  by  bacterial  con- 
tamination may  be  rendered  clear  by  filtration  through  a  Pasteur- 
Chamberland  filter  or  by  centrifugalization.  Clouding  from  this 
cause  does  not  occur  within  the  arbitrary  three-hour  time  limit  of 
the  test. 

2.  Preservatives  and  Solvents.— As  stated  above,  various  chemi- 
cals used  for  preserving  the  antiserum  and  for  dissolving  the  sus- 
pected stains  may  lead  to  wrong  inferences. 

3.  Hyperacidity  and  Hyper  alkalinity. —The  solution  of  the 
stain  should  be  neutral  in  reaction,  feebly  acid,  or  feebly  alkaline. 

1  In  the  case  of  old,  difficultly  soluble  stains  Uhlenhuth  uses  a  one  per  cent, 
aqueous  solution  of  sodium  hydrate,  while  Ziemke  prefers  a  concentrated  solution 
of  potassium  cyanid,  with  subsequent  neutralization  with  tartaric  acid.  These 
chemicals,  though  active  solvents  for  old  blood  stains,  are  not  dependable,  because 
of  their  likelihood  to  cause  false  reactions  with  various  antisera.  Graham-Smith 
and  Sanger  obtained  precipitates  with  solutions  of  potassium  cyanid  (one  per  cent.), 
tartaric  acid  (0.1  per  cent.),  and  sodium  hydrate  (o.r  per  cent.).  In  medico-legal 
work  it  is  safe  to  be  guided  by  Nuttall's  advice,  and  refuse  to  submit  to  the  test 
bloods  which  are  insoluble  in  normal  salt  solution 


MEDICO-LEGAL  TESTS  FOR  BLOOD. 


121 


If  too  highly  acid  or  alkaline,  positive  reactions  may  occur  with 
unrelated  blood. 

4.  Contamination  oj  the  Specimen. — Human  albumins  and 
various  chemicals  may  be  mixed  with  the  suspected  blood  stain  or 
may  resemble  it,  and  in  forensic  work  their  presence  must  be  ab- 
solutely excluded  by  appropriate  tests.  Nuttall1  found  that  tannin 
especially  causes  decided  clouding  even  in  1  :  1000  dilutions,  and 
that  solutions  contaminated  with  yellow  polished  leather  acted 
similarly.  He  found  that  human  blood  mixed  with  shoe  polish, 
and  blood  allowed  to  dry  upon  black  leather,  wall-paper,  various 
dress  fabrics,  rubber,  oil-cloth,  silver  and  copper  coins,  coal,  wood, 
and  other  substances,  reacted  typically  with  human  antiserum. 
The  clouding  due  to  the  admixture  of  earth  (referable  to  the 
presence  of  lime  salts)  Nuttall  obviates  by  saturating  with  carbon 
dioxid  and  subsequent  filtration. 

Old  blood  stains,  except  that  they  develop  the  precipitate 
slowly,  react  like  fresh  blood.  Ziemke2  examined  stains  known  to 
be  twenty-five  years  old  and  obtained  positive  findings.  Accord- 
ing to  J.  Meyer,3  even  solutions  of  the  muscular  tissues  of  five- 
thousand-year-old  mummies  react  positively!  Uhlenhuth4  found 
that  specimens  could  be  frozen  for  two  weeks  at  a  temperature  of 
— io°  C.  without  in  any  manner  affecting  the  sensitiveness  of 
the  reaction,  and  that  blood  mixed  with  soapy  water,  menstrual 
urine,  and  other  contaminating  fluids  responds  typically  and 
promptly.  Nuttall  and  Dinkelspiel5  demonstrated  that  human 
blood  mixed  with  the  blood  of  different  animals  (sheep,  oxen, 
horses,  and  dogs)  reacts  characteristically  with  human  antiserum. 
Dried  blood  crusts  subjected  to  an  hour's  heating  at  1300  C.  do 
not  respond  to  the  test. 

Value  of  the  Test. — The  Bordet  reaction  has  already  figured  in 
three  murder  trials  in  this  country,6  and  in  these  cases  it  has  been 
accepted  by  the  Court  as  valid  evidence.  In  order  to  insure  in- 
fallibility, faultless  technic,  bred  only  of  long  and  intelligent 
experience,  is  one  of  the  first  essentials.  This  acquired,  the  ex- 
aminer must  exclude  every  source  of  error  outlined  above,  and 
consider  as  positive  only  those  reactions  which,  with  proper  dilution, 
afford  a  turbidity  and  distinct  precipitate  within  the  prescribed 
time  limit,  the  behavior  of  the  several  controls  being  consistent 
with  that  of  the  main  test.    Under  these  conditions  a  solution 

1  Loc.  cit. 

2  Deutsch.  med.  Wochenschr.,  1901,  vol.  xxvii,  pp.  424  and  731. 

3  Munch,  med.  Wochenschr.,  1904,  vol.  li,  p.  663. 

*  Loc.  cit.  5  Brit.  Med.  Jour.,  1901,  vol.  i,  p.  1141. 

6  1901,  State  of  Maine  vs.  Lambert  (Whittier);  1903,  State  of  Del.  vs.  Collins 
(Robin);  1903,  Commonwealth  of  Penna.  vs.  Bechtel  (Lear). 


122     EXAMINATION  OF  THE  BLOOD  BY  CLINICAL  METHODS. 


proved  to  be  blood  which  reacts  typically  with  human  antiserum 
may  surely  be  pronounced  of  human  origin. 

The  agglutination  of  human  erythrocytes  after 
Hanging-     their  admixture  with  alien  serum  and  the  absence 
drop  Test,    of  this  change  on  the  addition  of  homologous 
serum  may  be  observed  under  the  microscope. 
This  fact  was  first  noted  by  Marx  and  Ehrnrooth,1  who  use  the 
principle  as  the  basis  for  the  following  simple  test  for  identifying 
blood  stains. 

The  suspected  blood  stain  is  dissolved  with  a  small  quantity 
of  normal  salt  solution  mixed  with  an  equal  amount  of  fresh 
human  blood,  and  of  this  solution  a  hanging-drop  preparation  is 
made  and  examined  under  the  microscope  with  a  -^--inch  objective. 
If  the  stain  tested '  is  human  blood,  the  erythrocytes  of  the  added 
fresh  blood  remain  unclumped  at  the  end  of  fifteen  minutes'  time, 
while  if  •  it  is  alien  blood,  they  become  distinctly  agglutinated  within 
this  period.  Monkeys'  blood,  although  it  fails  to  clump  the 
erythrocytes,  causes  them  to  shrink  and  to  become  polygonal  in 
shape.  The  writer  can  confirm  this  test,  so  far  as  human  blood  is 
concerned,  but  its  medico-legal  value  must  remain  undetermined 
until  further  studies  have  been  made.  The  reaction  should  be 
controlled  by  Bordet's  test,  for  which  it  is  in  no  sense  a  substitute. 

OTHER  METHODS  OF  BLOOD  EXAMINATION. 

Numerous  methods  of  blood  analysis  other  than  those  de- 
scribed in  this  section  have  also  been  devised,  more  especially 
for  scientific  investigation  than  for  clinical  use.  Their  detailed 
description  not  being  germane  to  the  plan  of  this  book,  the  reader 
is  referred  to  the  original  articles  for  exact  data.  Among  these 
non-clinical  methods  of  research  are  included  the  estimations  of 
the  total  volume  of  blood  (Haldane  and  Smith2);  of  the  amount  of 
solids  (Stintzing 3) ;  of  the  percentage  of  blood  iron  (Jolles 4) ;  of  the 
quantity  of  fat  and  fatty  acids  in  the  blood  (Engelhardt 5) ;  of  the 
blood  viscosity  (Hirsch  and  Beck6) ;  of  the  osmotic  tension  of  the 
plasma  (Hamburger7;  de  Vries8);  and  of  the  resistance  of  the 
erythrocytes  to  the  action  of  electricity,  heat,  and  mechanical 
injury  (Laker9 ;  Maragliano 10). 

1  Munch,  med.  Wochenschr.,  1904,  vol.  li,  p.  293. 

2  Jour.  Physiol.,  1900,  vol.  xxv,  p.  311. 

3  Verhandl.  d.  XII.  Cong.  f.  inn.  Med.,  1893. 
*  Arch,  f .  med.  Exp.,  vol.  xiv,  p.  73. 

5  Deutsch.  Arch.  f.  klin.  Med.,  1901,  vol.  lxx,  p.  182. 

6  Ibid.,  1901,  vol.  lxix,  p.  503.       7  Centralbl.  f.  Physiol.,  1893,  vol.  vii,  p.  656. 

8  Jahrb.  f.  w.  Botanik,  1884,  vol.  xiv,  p.  427. 

9  Wien.  med.  Presse,  1890,  vol.  xxxi,  p.  1375. 

10  Berlin,  klin.  Wochenschr.,  1887,  vol.  xxiv,  p.  797. 


SECTION  II. 


THE  BLOOD  AS  A  WHOLE. 


SECTION  II. 
THE  BLOOD  AS  A  WHOLE. 


I.  GENERAL  COMPOSITION. 

Blood  is  a  tissue  consisting  of  fluid  and  cor- 
Plasma,  Serum,  puscular  elements,  the  former  constituting  about 
and  Cells.  three-fifths,  and  the  latter  two-fifths,  of  its  total 
volume.  It  has  been  approximated  that  the  total 
quantity  of  blood  in  the  normal  individual  is  from  one-twelfth  to 
one-fourteenth  of  the  body-weight,  the  proportion  being  somewhat 
less  in  the  infant  than  in  the  adult.  Much  lower  proportions 
than  these  were  determined  by  Haldane  and  Smith,1  who  found 
that  in  health  the  bulk  of  blood  ranged  from  one-thirtieth  to  one- 
sixteenth  of  the  body- weight  (3.34  to  6.27  per  cent.),  these  figures 
having  been  calculated  by  a  method  based  upon  the  capacity  of 
the  blood  to  absorb  CO  2  •  The  fluid  element  of  the  blood,  known 
as  the  plasma  or  liquor  sanguinis,  is  an  alkaline,  yellowish  liquid, 
of  a  specific  gravity  ranging  from  about  1.026  to  1.030,  and 
containing  approximately  10  per  cent,  of  solid  matter,  of 
which  three-fourths  are  proteids,  consisting  of  fibrinogen,  serum 
albumin,  and  serum  globulin.  Coagulation  of  the  blood  results 
in  its  separation  into  a  densely  reticulated,  somewhat  granular 
substance,  fibrin,  and  into  a  clear,  straw-colored,  alkaline  fluid, 
serum.  Fibrin  is  a  sparingly  soluble,  highly  elastic,  proteid  body, 
which  incloses  and  imprisons  within  its  multitude  of  delicate 
fibrils  the  corpuscular  elements,  the  whole  forming  the  blood  clot 
or  crassamentum.  Serum  is  a  clear,  straw-colored,  alkaline  fluid, 
having  a  specific  gravity  of  about  1.026  and  containing  practically 
the  same  amount  of  solids  and  relative  proportion  of  proteids  as  are 
found  in  the  plasma  ;  its  proteid  constituents  are  fibrin  ferment, 
which  replaces  the  fibrinogen  of  the  plasma,  serum  albumin, 
and  serum  globulin. 

The  corpuscular  elements  of  the  blood  are  free  cellular  bodies 
suspended  in  the  plasma.  They  are  of  two  varieties  :  the  eryth- 
rocytes or  red  corpuscles,  and  the  leucocytes  or  white  corpuscles. 

1  Jour.  Physiol.,  1900,  vol.  xxv,  p.  33. 
125 


126 


THE  BLOOD  AS  A  WHOLE. 


In  addition  to  these  cells,  two  other  elements  are  also  found, 
namely,  the  blood  plaques  and  the  •  hemokonia,  although  these 
bodies,  while  they  may  be  conveniently  grouped  with  the  red  and 
white  cells,  are  not  to  be  regarded  as  definite  corpuscular  entities. 

The  salts  of  the  blood  include  sodium  chlorid,  potassium 
chlorid,  sodium  carbonate,  sodium  phosphate,  magnesium  phos- 
phate, calcium  phosphate,  and  sulphates  ;  of  these  salts,  sodium 
chlorid  is  the  most  abundant,  constituting  from  60  to  90  per 
cent,  of  the  total  amount  of  mineral  matter. 

Certain  extractives  are  also  found,  among  which  are  urea  and 
uric  acid,  creatin,  creatinin,  xanthin,  hypoxanthin,  sugar,  fats, 
soaps,  and  cholesterin. 

The  gases  of  the  blood  consist  of  oxygen,  nitrogen,  and  carbon 
dioxid,  the  oxygen  existing  chiefly  in  combination  with  hem- 
oglobin in  the  erythrocytes,  and  the  carbon  dioxid  as  carbonates  ; 
the  nitrogen  is  held  in  simple  solution.  About  60  volumes  of  gas 
are  contained  in  each  100  volumes  of  blood.  Arterial  blood  con- 
tains roughly  20  volumes  of  oxygen  and  40  of  carbon  dioxid, 
while  venous  blood  contains  less  than  10  volumes  of  oxygen  and 
almost  50  of  carbon  dioxid  ;  the  quantity  of  nitrogen  in  both 
arterial  and  venous  blood  is  from  1  to  2  volumes. 

II.  COLOR. 

The  distinctive  color  of  the  blood  is  due  to 
Normal       the  presence  of  the  hemoglobin  contained  in  the 
Variations,    erythrocytes,  and  alterations  in  the  chemical  com- 
position of  this  pigment  produce  corresponding 
changes  in  the  color  of  these  cells,  and,  consequently,  in  the 
naked-eye  appearance  of  the  whole  blood.    The  color  of  arte- 
rial blood  is  bright  scarlet,  inasmuch  as  it  contains  a  large  amount 
of  oxygen  in  chemical  combination  with  the  hemoglobin  ;  while 
venous  blood,  on  the  other  hand,  is  of  a  dark,  purplish-blue  tint, 
owing  to  its  deficiency  in  oxygen  and  to  the  presence  of  more  or 
less  uneliminated  carbon  dioxid.    This  difference  in  color  is  so 
obvious  that  a  cursory  glance  suffices  to  distinguish  arterial  and 
venous  bloods. 

The  presence  of  immense  numbers  of  hemo- 
Density       globin- containing  elements  accounts  for  the  vary- 
and  ing  degree  of  density  and  opacity  which  the 

Opacity.      blood  possesses,  distinguishing  it  from  a  mere 
transparent,  colored  fluid.  If,  for  any  reason,  the 
hemoglobin  escapes  from  the  erythrocytes  into  the  surrounding 
plasma,  this  characteristic  opacity  is  quickly  lost,  and  the  blood 


ODOR  AND  VISCOSITY. 


127 


becomes  transparent  and  of  a  "  laky  "  color.  The  cells  are  laked 
by  the  influence  of  heat,  water,  fat  solvents,  and  hydrogen  and 
hydroxyl  ions,  all  of  which  act  upon  the  outer  semipermeable  layer 
of  the  cells'  stroma  and  thus  favor  hemoglobin  dissolution.  The 
density  and  the  opacity,  and,  consequently,  the  color,  of  the  blood 
increase  and  diminish  according  to  the  fluctuations  which  occur 
in  the  relative  amounts  of  plasma  and  erythrocytes,  and  also 
according  to  the  cells'  richness  in  hemoglobin,  irrespective  of  their 
numerical  variation. 

In  anemic  conditions  the  blood  is  usually 
Pathological  pale  in  color,  somewhat  transparent,  and  thin 
Variations,  and  watery- looking.  This  is  the  case  particu- 
larly in  primary  pernicious  anemia,  in  chlorosis, 
and  in  leukemia ;  in  [the  first-named  disease  it  is  sometimes  difficult 
to  believe  that  the  watery,  pale  fluid  which  flows  from  the  puncture 
is  anything  but  pure  serum  ;  in  leukemia  the  blood  drop  may  have 
a  peculiar  light,  mottled,  streaked  appearance,  or  a  uniform  milky- 
white  tint  may  predominate  over  the  normal  red  hue.  In  cases 
of  dyspnea,  arterial  blood,  because  of  its  inadequate  oxygenation, 
may  be  dark  blue,  closely  resembling  blood  from  the  veins.  This 
similarity  has  also  been  noted  in  cases  of  poisoning  by  sulphur- 
etted hydrogen,  in  which  condition  the  blood  may  even  be  changed 
to  a  dark  greenish  tint.  In  some  cases  of  diabetes  mellitus  the 
presence  of  large  quantities  of  free  fat  in  the  circulation  seem- 
ingly divides  the  blood  drop  into  two  distinct  layers — an  upper, 
light-colored  portion,  containing  supernatant  fat  droplets,  and  a 
lower,  darker  layer  of  pure  blood  ;  at  first  glance  diabetic  blood 
may  be  somewhat  pinkish  or  salmon-colored. 

In  poisoning  by  anilin,  nitrobenzol,  hydrocyanic  acid,  and  potas- 
sium chlorate  the  blood  is  chocolate-  or  dun-colored  ;  and  in 
poisoning  by  carbon  monoxid,  bright  cherry-red.  In  severe 
icterus  a  yellowish-red  tint  of  the  blood  has  been  observed. 

III.  ODOR  AND  VISCOSITY. 

Owing  to  the  presence  of  certain  volatile  fatty  acids  blood 
possesses  a  peculiar  and  characteristic  odor  or  halitus,  which  may 
be  intensified  by  the  addition  of  concentrated  sulphuric  acid,  and 
which  rapidly  disappears  after  the  withdrawal  of  the  blood  from 
the  body.  The  slippery,  greasy  feeling  of  freshly  drawn  blood  is 
quickly  lost  after  its  exposure  to  the  atmosphere,  and  is  replaced  by 
a  viscosity,  or  stickiness,  as  coagulation  progresses.  The  viscosity 
of  the  whole  blood  is  apparently  influenced  to  a  large  extent  by 
the  cellular  elements,  chiefly  by  the  erythrocytes,  although  the 


128 


THE  BLOOD  AS  A  WHOLE. 


viscosity  of  the  serum  must  also  be  regarded  as  a  determining 
factor  of  more  or  less  importance. 

Hirsch  and  Beck1  have  determined  that  the  "viscosity  value," 
as  they  term  it,  of  human  blood  is  about  five  times  that  of  distilled 
water — i.  e.,  the  viscosity  of  blood  having  a  specific  gravity  rang- 
ing between  1.045  and  1-055  is  expressed  by  the  figure  5.1,  in 
comparison  with  that  of  water,  which  equals  1,  the  temperature 
of  both  fluids  being  the  same,  380  C.  Although  no  close  relation- 
ship can  be  distinguished  between  the  degree  of  viscosity  and  the 
specific  gravity  of  the  blood,  these  experimenters  have  apparently 
proved  that  the  lower  the  density  of  the  blood,  the  less  marked 
its  adhesiveness.  This  quality  is  exaggerated  in  individuals  living 
upon  a  largely  nitrogenous  diet,  and  it  is  greatly  modified  by  star- 
vation. S.  Weir  Mitchell2  has  observed  that  hyperviscosity 
develops  when  blood  is  subjected  to  the  direct  action  of  snake 
venom,  while  Stengel3  has  noted  a  similar  condition  resulting 
from  contaminating  fresh  blood  with  the  serum  of  patients  suffer- 
ing from  chlorosis,  pernicious  anemia,  and  leukemia.  Any  one 
who  has  done  much  blood  work  is  familiar  with  the  marked 
fluidity  of  the  fresh  specimen  in  the  high-grade  anemias,  and 
with  the  diminished  viscosity  of  the  erythrocytes  and  their  dis- 
inclination to  form  rouleaux  under  such  circumstances. 


IV.  REACTION. 

Under  normal  conditions  the  reaction  of  the 
Reaction     blood  is  alkaline,  owing  chiefly  to  the  presence 
in  Health,    of  sodium  carbonate  and  disodium  phosphate. 

Clinically,  the  degree  of  alkalinity  is  determined 
by  ascertaining  the  amount  of  sodium  hydroxid  which  is  exactly 
neutralized  by  100  c.c.  of  blood,  the  result  being  usually  expressed 
in  milligrams  of  NaOH  per  100  c.c.  of  blood.  The  figures  given 
by  different  investigators  as  representing  the  normal  alkalinity 
range  within  the  widest  limits,  chiefly  in  consequence  of  the  many 
different  methods  by  which  such  data  were  obtained.  In  view 
of  these  marked  discrepancies  the  alkalinity  figures  of  different 
workers  are  in  no  sense  comparable  unless  they  are  based  upon 
precisely  similar  methods  of  investigation  pursued  with  identical 
technic.    The  following  table,  compiled  from  reliable  data,  illus- 

1  Deutsch.  Arch.  f.  klin.  Med.,  1901,  vol.  lxix,  p.  503. 

2  Mitchell  and  Stewart,  "A  Contribution  to  the  Study  of  the  Effect  of  the 
Venom  of  Crotalus  adamanteus  upon  the  Blood,"  Washington,  1898. 

3  "Twentieth  Century  Practice  of  Medicine,"  New  York,  1896. 


REACTION. 


129 


trates  the  range  of  the  normal  blood  alkalinity  as  estimated  by 
various  observers : 


Observes.  Degree  or  Alkalinity. 

Kraus  162-232  mgm.  NaOH  per  100  c.c.  of  blood. 

Burmin  182-218    "  "       "     "    "    "  " 

Rumpff  182-218    "  "       "     "    "    "  " 

Jeffries  200 

Freudberg  200-240  " 

Lepine  203 

Canard  203-276    "         "       "     "  " 

Drouin  206 

Von  Limbeck  218 

Zuntz  and  Lehmann  240 

Orlowsky  -  240-267  " 

Von  Jaksch  260-300  " 

Schultz-Schultzenstein  260-300  " 

Dare  266 

Strauss  300-350  " 

Brandenburg  33°_37°  " 

Lowy  449 

Berend  450-500  " 

Engel  479-533  " 

Mya  and  Tassinari  616  "  "        "     "    "    "  1 


With  the  titration  method,  now  generally  admitted  to  furnish 
fairly  accurate  results,  appreciably  higher  figures  are  obtained 
with  laked  whole  blood  than  with  serum  alone,  since  by  the 
former  method  the  alkalinity  of  all  the  plasma  and  cellular  ele- 
ments is  estimated,  while  by  the  latter  the  influence  of  the  cor- 
puscles is  entirely  eliminated. 

The  alkalinity  of  the  blood  is  slightly  higher, 
Physiological  as  a  general  rule,  in  men  than  in  women  and 
Variations,  children,  and  is  somewhat  influenced  by  the  time 
0]  day,  being  at  its  minimum  during  the  early 
morning  hours,  gradually  rising  during  the  afternoon,  and  falling 
again  during  the  evening.  Some  observers  maintain  that  it  is 
increased  during  the  -period  of  digestion,  but  this  fact  is  disputed 
by  others.  It  is  temporarily  diminished  by  the  effects  of  mus- 
cular exercise  and  by  a  diet  deficient  in  nitrogenous  substances; 
on  the  contrary,  richly  nitrogenous  jood  eaten  during  the  per- 
formance of  muscular  work  overcomes  the  effect  of  such  exertion 
in  lowering  the  alkalinity.  The  effects  of  cold  baths  are  said  to 
increase  the  alkalinity  of  the  blood.  Orlowsky,1  from  a  study 
of  63  cases  of  various  maladies,  concludes  that  the  degree  of 
blood  alkalinity  is  proportional  to  the  erythrocyte  count,  but  that 
it  bears  no  relation  to  the  number  of  leucocytes. 

In  health,  by  the  perfect  mechanism  of  the  emunctory  organs 
of  the  body,  the  normal  balance  of  blood  alkalinity  is  constantly 
1  Deutsch.  med.  Wochenschr.,  1903,  vol.  xxix,  p.  601. 

9 


THE  BLOOD  AS  A  WHOLE. 


maintained,  in  spite  of  the  entrance  of  acids  into  the  blood, 
whether  by  the  ingestion  of  acid  substances  or  by  their  produc- 
tion within  the  system,  for  the  hyperacidity  from  such  causes 
is  promptly  removed  from  the  blood  by  the  action  of  the  kidneys, 
the  skin,  and  the  lungs.  Thus,  the  ingestion  of  acids  is  quickly 
followed  by  increased  acidity  of  the  urine  and  sweat,  while  at  the 
same  time  an  increased  quantity  of  carbon  dioxid  is  given  off  by 
the  lungs.  It  is  probable  that  the  tendency  to  acidity  is  partly 
neutralized  by  the  ammonium  salts  generated  from  proteid  foods, 
and  also  by  the  action  of  the  liver.  The  blood  alkalinity  may 
be  transiently  increased  by  administering  an  alkali  internally  or 
by  enema,  the  latter  method  having  the  more  pronounced  effect, 
according  to  Orlowsky.1 

Increased  alkalinity  goes  hand  in  hand  with  increased  antidotal 
action  of  the  blood  against  bacterial  infection,  as  experiments  have 
shown  that  animals  whose  blood  had  been  artificially  rendered 
highly  alkaline  by  the  administration  of  sodium  salts,  showed 
much  greater  resistance  to  the  effects  of  virulent  micro-organisms 
than  untreated  animals.  Therefore,  it  is  believed  that  the  power 
of  immunity  against  infections  may,  to  a  certain  degree,  be  meas- 
ured by  the  alkalinity  of  the  blood,  for,  in  animal  experimenta- 
tion, the  fact  is  evident  that  the  greatest  degree  of  blood  alka- 
linity is  found  in  animals  whose  immunity  is  absolute.  The  rat, 
which  is  naturally  immune  to  anthrax,  has  excessively  alkaline 
blood  and  other  body  fluids.  This  hyperalkalinity,  however,  does 
not  protect  this  rodent  against  plague.  An  excess  of  alkali  in  the 
blood  is  probably  antidotal  to  invading  bacteria,  not  per  se,  but 
rather  because  of  its  power  to  dissolve  and  liberate  cell  nucleins, 
which,  as  alexins,  are  directly  bactericidal. 

Unfortunately,  the  question  of  alteration  in  the 
Pathological  alkalinity  of  the  blood  in  various  pathological 
Variations,    conditions  is  at  the  present  time  one  about  which 
the  opinions  of  different  observers  conflict,  so 
that  conclusions  concerning  this  subject  must  be  accepted  with 
more  or  less  reserve. 

It  is  of  interest,  however,  to  note  that  most  observers  agree 
that,  as  a  rule,  the  alkalinity  of  the  blood  is  perceptibly  lowered 
in  those  diseases  associated  with  a  febrile  movement,  but  no  defi- 
nite relation  between  the  intensity  of  the  pyrexia  and  the  degree 
of  lessened  alkalinity  has  been  established.  Auerbach,2  having 
noted  that  a  temperature  of  1080  F.  renders  alkaline  culture  media 
bactericidal,  argues  that  in  acute  infections  the  pyrexia,  although 
it  diminishes  the  alkalinity  of  the  blood,  at  the  same  time  may  be 

1  Loc.  cit.  2  Abst.  in  Jour.  Amer.  Med.  Assoc.,  1903,  vol.  xli,  p.  11 22. 


REACTION. 


beneficial,  in  that  it  also  increases  its  bactericidal  action.  Sub- 
normal alkalinity  figures  have  also  been  met  with  in  the  primary 
and  secondary  anemias,  with  the  exception  of  chlorosis,  in  which 
condition  the  blood  alkalinity  usually  is  either  normal  or  perhaps 
slightly  increased.  Desevres1  has  drawn  attention  to  the  fact 
that  in  the  early  stages  of  acute  diseases  the  alkalinity  is  either 
normal  or  somewhat  increased,  and  in  the  majority  of  instances 
it  becomes  perceptibly  diminished  during  convalescence.  In 
chronic  diseases  it  is  usually  decreased  if  the  duration  of  the  dis- 
ease has  been  of  long  standing. 

Drouin2  found  a  lessened  alkalinity  of  the  blood  in  enteric 
fever,  pneumonia,  malarial  fever,  diphtheria,  rheumatic  fever,  ery- 
sipelas, appendicitis,  and  in  many  other  acute  infections.  Can- 
tani3  maintains  that  in  the  algid  stage  of  Asiatic  cholera  the 
reaction  of  the  blood  during  life  in  some  cases  may  be  even 
acid,  and  that  the  alkalinity  is  always  markedly  reduced.  Von 
Jaksch,4  Peiper,5  Kraus,6  and  others  state  that  the  alkalinity 
is  generally  diminished  in  uremia,  diabetes,  osteomalacia,  organic 
diseases  of  the  liver,  and  in  poisoning  by  carbon  monoxid  and 
by  phosphorus,  especially  by  the  latter.  Decreased  alkalin- 
ity has  also  been  noted  in  cholemia,  Addison's  disease,  Hodg- 
kirfs  disease,  poisoning  by  mineral  acids,  the  late  stages 
of  malignant  neoplasms,  and  in  various  long-standing  cachectic 
conditions.  Thomas7  found  the  alkalinity  reduced  in  acute 
alcoholism  and  as  the  result  of  chloroform  narcosis.  Tchlenorff8 
found  a  diminished  alkalinity  in  a  wide  variety  of  skin  diseases, 
among  which  are  named  psoriasis,  eczema,  pemphigus,  purpura 
hcemorrhagica,  erythema  multiforme,  lichen  rubra,  and  elephantiasis. 
Since  it  was  also  found  that  the  administration  of  arsenic  failed 
to  increase  the  blood  alkalinity,  the  action  of  this  drug  upon 
dermatoses  is  evidently  not  due  to  its  influence  upon  the  blood. 

In  organic  diseases  of  the  heart  unassociated  with  pyrexia  and 
in  nervous  diseases  the  alkalinity  of  the  blood  has  been  found  to 
be  increased.  In  chronic  rheumatism  and  in  renal  lesions  unac- 
companied by  uremic  symptoms  the  reaction  of  the  blood  is  usu- 
ally found  to  be  unaltered. 

1  These  de  Lyon,  1897-98. 

2  "Hemo-alcalimetrie  et  Hemo-acidimetrie,"  These  de  Paris,  1892,  No.  83. 

3  Centralbl.  f.  d.  med.  Wissensch.,  1884,  vol.  xxii,  p.  785. 

4  Deutsch.  med.  Wochenschr.,  1893,  vol.  xix,  p.  10. 

5  Arch.  f.  pathol.  Anat.,  1889,  vol.  cxvi,  p.  337. 

6  Zeitschr.  f.  Heilk.,  1889,  vol.  x,  p.  106. 

7  Arch.  f.  exper.  Pathol,  u.  Pharm.,  1898,  vol.  xli,  p.  1. 

8Russkiy  Vrach,  1898,  vol.  xix,  p.  248;  abst.  in  Jour.  Cutan.  and  Genito- 
Urin.  Dis.,  1898,  vol.  xvi,  p.  544. 


132 


THE  BLOOD  AS  A  WHOLE. 


V.  SPECIFIC  GRAVITY. 

In  the  majority  of  healthy  male  adults  the 
Normal      specific  gravity  of  the  blood  varies  from  1.055  to 
Range.       1.065,  the  average  being  in  the  neighborhood  of 
1 .060.    In  women  the  average  is  somewhat  less — ■ 
about  1.056;  in  children  it  is  about  1.05 1;  and  in  new-born  injants 
1.066  is  considered  normal.    Diurnal  variations  in  the  specific 
gravity  have  been  noted,  but  these  fluctuations  are  slight  and 
unimportant.    The  blood  density  of  habitual  dwellers  in  high  alti- 
tudes is  distinctly  increased.    Lloyd  Jones1  and  Schmaltz2  found 
that  muscular  exercise,  if  moderate,  lowers  the  blood  density,  but 
if  prolonged  and  attended  by  free  sweating,  distinctly  increases  it. 
Venous  blood  is  said  to  be  of  slightly  higher  specific  gravity  than 
arterial.    The  average  specific  gravity  of  the  blood  of  the  two 
sexes,  as  determined  by  the  principal  observers,  is  as  follows: 


Authority.  Males.  Females. 

Askanazy  1060.1  1056.4 

Schmidt  1060.0  1050.0 

Hammerschlag  1061.5  io57-5 

Lloyd  Jones  1058.5  105 1.5 

Landois  1057.5  1056.0 

Becker  1057.0  1056.5 

Schmaltz  1057.0  1056.0 

Peiper  1055.0  1053.0 


From  a  clinical  standpoint  the  specific  gravity 
Pathological  of  the  blood  may  be  regarded,  within  certain 
Variations,  limits,  as  a  tolerably  accurate  index  to  the 
corpuscular  richness  of  this  tissue  and  to  the 
hemoglobin  equivalent  of  the  erythrocytes,  since  fluctuations  in 
these  constituents  immediately  give  rise  to  corresponding  altera- 
tions in  the  density  of  the  blood  mass.  It  follows,  then,  that  in 
the  various  conditions  of  anemia,  characterized  by  corpuscular 
and  hemoglobin  losses,  low  specific  gravities  are  encountered; 
on  the  other  hand,  it  is  also  obvious  that  in  conditions  of  polycy- 
themia the  cellular  increase  and  the  high  hemoglobin  equivalent 
are  mirrored  by  the  corresponding  rise  in  the  density  of  the 
blood.  An  increase  promptly  follows  any  sudden  drain  upon 
the  fluids  of  the  system  sufficient  to  cause  inspissation  of  the 
blood,  such  as  may  result  from  copious  diarrhea,  free  sweating, 
or  hyperemesis;  while  the  density  is  at  once  lowered  as  the  re- 
sult of  sudden  dilution  of  the  blood,  following,  for  example,  the 
injection  of  a  large  quantity  of  saline  solution  or  even  the  inges- 

1  Jour.  Physiol.,  1887,  vol.  viii,  p.  1. 

2  Deutsch.  Arch.  f.  klin.  Med.,  1890,  vol.  xlvii,  p.  145. 


SPKCIFir  (1  RAVI  TV. 


133 


tion  of  a  large  volume  of  liquid.  Fluctuations  in  the  specific 
gravity  of  the  blood  under  such  circumstances,  which  are  purely 
physiological  in  character,  are  invariably  of  transient  duration, 
for  the  normal  relation  between  the  relative  volumes  of  corpuscles 
and  plasma  becomes  quickly  reestablished  by  means  of  the  liquid 
interchange  between  the  tissues  and  the  blood  vessels. 

Owing  to  the  fact  that  in  most  instances  a  close  relationship 
exists  between  the  amount  of  hemoglobin  and  the  specific  gravity, 
some  investigators  are  accustomed  to  take  this  parallelism  as  a 
basis  for  calculating  the  percentage  of  hemoglobin  in  the  blood. 
Thus,  by  determining  the  specific  gravity  and  by  comparing  the 
figure  thus  obtained  with  a  table  giving  the  hemoglobin  equiva- 
lents corresponding  to  varying  degrees  of  blood  density,  fairly 
accurate  results  have  been  obtained.  The  following  hemoglobin 
equivalents  of  different  specific  gravities  of  the  blood  have  been 
determined  by  Hammerschlag1  and  by  Lichty.2 


Hammerschlag.  Lichty. 


Specific  gravity. 

Hemoglobin  equivalent. 

Specific  gravity. 

Hemoglobin  equivalent. 

i°33-io35 

25-30  per  cent. 

30-35   "  " 

1035-1038 

25-30  per  cent. 
30-40  "  " 

1035-1038 

1038-1043 

1038-1040 

35-40   "  " 

1043-1045 

4o-45   "  " 

1 040-1 045 

40-45  " 

1045-1047 

45-5o  " 

1045-1048 

45-55   "  " 

1047-1049 

5o-53   "  " 

1048-1050 

55-65   "  " 

1049-1052 

55-65   "  " 

1050-1053 

65-70  "  " 

1052-1054 

65-70   "  " 

i°53-i°55 

7o-75   "  " 

1054-1056 

7o-75   "  " 

io55-io57 

75-85   "  " 

1056-1060 

75-85   "  " 

105 7-1060 

85-95   "  " 

1060-1063 
1063-1065 

85-95   "  " 
95-100  "  " 

It  will  be  noted  that  in  both  these  tables  the  variations  in 
density  are  somewhat  greater  in  high  than  in  low  hemoglobin 
percentages.  It  has  been  stated  by  Diabella3  that,  on  the  aver- 
age, a  difference  of  10  per  cent,  in  hemoglobin  corresponds  to 
4.46  parts  per  thousand  in  specific  gravity,  and  that  differences 
amounting  to  from  3  to  5  parts  per  thousand  in  the  specific  grav- 
ity may  arise  from  the  influence  of  the  stroma  of  the  erythrocytes, 
in  blood  characterized  by  a  striking  disturbance  in  the  parallelism 
which  normally  exists  between  these  cells  and  the  hemoglobin. 

In  the  clinical  application  of  this  indirect  method  of  computing 
hemoglobin  percentages  several  conditions,  in  which  factors  other 
than  the  presence  of  hemoglobin  in  the  erythrocytes  influence  the 
specific  gravity,  must  be  excluded.  In  leukemia,  for  example,  it 
will  be  found  that  hemoglobin  percentages  based  on  the  above 
tables  are  much  higher  than  actually  exist,  the  cause  of  this  fal- 

1  Loc.  cit.  2  Phila.  Med.  Jour.,  1898,  vol.  ii,  p.  242. 

3  Deutsch.  Arch.  f.  klin.  Med.,  1896,  vol.  lvii,  p.  302. 


134 


THE  BLOOD  AS  A  WHOLE. 


lacy  being  the  presence  of  enormous  numbers  of  leucocytes  in  the 
blood;  in  pernicious  anemia  the  hemoglobin  is  frequently  higher 
than  the  specific  gravity  indicates,  for  in  this  disease  the  individual 
corpuscles  are  much  richer  in  hemoglobin  than  normally;  and 
in  conditions  associated  with  extensive  dropsy  the  hemoglobin 
percentage  does  not  parallel  the  specific  gravity,  owing  to  the 
abnormally  high  proportion  of  fluids  in  the  blood  mass. 

These  three  sources  of  error,  aside  from  the  rather  trying  tech- 
nic by  which  one  must  first  determine  the  specific  gravity  of  the 
blood  drop  (see  p.  94),  are  sufficient  to  make  most  workers 
reluctant  to  adopt  this  method  as  a  substitute  for  the  hemometer. 


VI.  FIBRIN  AND  COAGULATION. 

The  essential  factor  of  coagulation  of  the  blood  is  the  forma- 
tion of  fibrin,  a  proteid  substance,  produced  in  the  plasma  after 
the  withdrawal  of  the  blood  from  the  body,  by  complex  chemical 
changes  occurring  between  the  soluble  calcium  salts  and  the 
nucleoproteids  of  the  blood,  with  the  consequent  production  of  a 
fibrin  ferment.  The  theories  regarding  coagulation  are  numer- 
ous, conflicting,  and  unsatisfactory,  and  must  necessarily  remain 
disputed  points  until  our  present  uncertain  knowledge  of  the 
chemistry  of  the  blood  proteids  becomes  fuller  and  more  definite.1 
Coagulation  is  delayed  and  imperfect  in  hemoglobinemia,  in  as- 
phyxia, in  jaundice,  in  conditions  of  general  dropsy,  and  in  in- 
dividuals who  are  prone  to  bleed  freely  from  trivial  wounds.  A 
similar  effect  is  produced  by  the  administration  of  alcohol.  Lamb2 
has  found  that  the  venom  of  certain  poisonous  snakes  conspicu- 
ously affects  clotting.  Cobra  venom  diminishes  coagulation  to  a 
marked  degree,  and  in  some  instances  may  even  wholly  prevent  it. 
Intoxication  with  daboia  poison  (the  venom  of  Russell's  viper)  acts 
variously,  according  to  the  quantity  injected.  In  small  doses  it 
hinders  coagulation  and  causes  the  formation  of  soft,  loose  clots; 
but  in  large  doses  this  venom  so  increases  the  coagulability  of 
the  blood  as  to  lead  to  fatal  intravascular  clotting.  Small  doses 
of  the  calcium  salts,  especially  the  chlorid,  promote  coagulation, 
but  the  opposite  effect  ensues  if  the  dose  is  too  large.  The 
administration  of  gelatin  usually  acts  in  the  same  manner,  be- 
cause, so  Gley 3  and  others  of  the  French  school  believe,  of  the  fact 

1  Schafer's  "Text  Book  of  Physiology,"  vol.  i,  Edinburgh  and  London,  1898, 
contains  a  complete  exposition  of  the  various  theories  of  coagulation  of  the  blood 
existing  up  to  the  present  time. 

2  Glasgow  Med.  Jour.,  1903,  vol.  lix,  p.  80. 

3  Sem.  med.,  1903,  vol.  xxiii,  p.  113. 


FIBRIN  AND  COAGULATION. 


135 


that  it  always  contains  from  2  to  5  per  cent,  of  calcium  chlorid. 
Brat 1  explains  the  therapeutic  action  of  gelatin  in  promoting  in- 
travascular clotting  by  assuming  that  it  contains  substances  which 
favor  the  deposit  of  plastic  material,  presumably  derived  from  the 
blood  cells,  at  the  site  of  the  clot.  The  studies  of  Boggs2  show  that 
gelatin  is  a  much  less  active  clotting  agent  than  calcium  chlorid, 
and  that  it  may  entirely  fail  to  act  in  some  cases.  Blood  coagu- 
lability as  a  factor  of  intestinal  hemorrhage  and  of  venous  throm- 
bosis in  enteric  fever  is  referred  to  elsewhere.    (See  Section  VII.) 

Carstairs  Douglas3  found  the  following  coagulation  figures  in 
healthy  women  and  in  normal  and  complicated  pregnancies: 


Group. 

Average 
Coagulation 
Time  in 
Minutes. 

Minimum. 

Maximum. 

Albuminurics  (16  cases): 

(a)  Pregnant  

5.60 

4.70 

7-5 

(6)  Puerperal  

7.00 

5.60 

10.0 

Eclampsias  (22  cases): 

(a)  Pregnant  

7.40 

4-5° 

9.0 

(b)  Puerperal  

7.00 

4-5° 

9-5 

Healthy  pregnant  women  (7  cases)  .... 

7.40 

5.00 

9.0 

Healthy  non-pregnant  "women  (7  cases) 

7-75 

5.00 

10.0 

From  these  findings  Douglas  concludes  that  the  thrombi 
found  in  various  organs  in  fatal  cases  of  eclampsia  are  not  due 
to  increased  intravascular  clotting. 

In  the  microscopical  examination  of  a  slide  of  fresh  blood 
fibrin  appears  as  extremely  delicate,  straight,  filamentous  lines 
which  cross  and  recross  the  field  in  every  direction.  It  forms 
a  network  of  fine,  interlacing,  fibrillary  bands,  in  the  clear  areas 
of  the  serum  intervening  between  the  masses  of  corpuscles,  some 
of  the  fibrin  threads  apparently  radiating  from  centers  consisting 
of  small  irregular  masses  of  blood  plaques.  The  relation  of  these 
islands  of  blood  plaques  to  coagulation  and  fibrin  formation,  if, 
indeed,  any  exists,  is  undetermined. 

In  normal  blood  the  formation  of  the  fibrin 
Hyperinosis  network  becomes  apparent  within  two  or  three 
and        minutes  after  exposure  of  the  blood  to  the  air, 
Hypinosis.    and  the  process  is  completed  within  about  six 
minutes.    In   certain   pathological  conditions, 
however,  both  the  length  of  time  required  for  its  formation 

1  Berlin,  klin.  Wochenschr.,  1902,  vol.  xxxix,  pp.  1146  and  11 70. 

2  Med.  News,  1904,  vol.  lxxxiv.,  p.  182.      3  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  709. 


136 


THE  BLOOD  AS  A  WHOLE. 


and  the  density  of  the  network  vary.  An  increase  in  the  amount 
of  the  fibrin  network  is  spoken  of  as  hyperinosis,  while  a  decrease 
in  fibrin  is  termed  hypinosis. 

In  general  terms  it  may  be  stated  that  fibrin 
Pathological  is  increased  in  acute  inflammatory  and  infectious 
Variations,   diseases,  especially  in  those  attended  by  an  ac- 
tive febrile  movement  and  by  exudative  proc- 
esses, the  amount  of  fibrin  roughly  corresponding  to  the  intensity 
of  the  process.    This  statement  is  made  with  certain  reserva- 
tions, for  the  rule  does  not  hold  true  in  all  such  instances,  as  is 


Fig.  39. — Normal  Blood. 
Showing  rouleaux  formation  and  fibrin  network. 


noted  below.  All  febrile  states  do  not  imply  a  fibrin  increase, 
for  none  is  found  in  the  fevers  associated  with  grave  cases  of 
chlorosis  and  of  pernicious  anemia.  Hayem  1  suggests  that  the 
density  of  the  fibrin  network  may  be  taken  as  an  indication 
of  the  individual's  resisting  powers  against  disease,  inasmuch 
as  it  appears  to  be  more  marked  in  the  blood  of  the  vigorous  than 
of  the  feeble.  In  acute  inflammations  accompanied  by  serous 
and  purulent  exudates  a  dense  fibrin  reticulum  is  observed,  the 
extent  of  the  exudation  being  in  a  degree  measured  by  the  density 

1  "Du  Sang,"  Paris,  1889. 


» 


FIBRIN  AND  COAGULATION.  137 

of  the  network.  Fibrin  is  increased  to  a  slighter  extent  in  par- 
enchymatous inflammations,  in  inflammations  of  the  mucous 
membranes  and  skin,  and  in  the  febrile  stages  of  chronic  sup- 
purations. Among  the  diseases  which  are  associated  with  an 
increase  in  fibrin  are  the  following :  abscess,  pneumonia,  rheumatic 
jever,  erysipelas,  acute  gout,  severe  angina,  bronchitis,  influenza, 
diphtheria,  pleurisy,  peritonitis,  pericarditis,  hepatitis,  meningitis, 
acute  gastritis,  enteritis,  cystitis,  vaginitis,  pustular  stage  of  variola, 
and  suppurating  tuberculous  cavities.  Fibrin  is  not  increased 
in  malignant  neoplasms,  enteric  fever,  malarial  fever,  tubercu- 
losis, pernicious  anemia,  leukemia,  chlorosis,  and  purpura.  In 


Fig.  40. — Hyperinosis. 
Showing  marked  increase  in  the  density  of  the  fibrin  network. 


parenchymatous  nephritis  it  is  but  slightly,  if  at  all,  increased, 
while  in*  interstitial  nephritis  the  increase  may  be  notable. 

Pfeiffer1  declares,  as  the  result  of  his  investigations,  that  in 
all  diseases  in  which  an  increase  of  fibrin  exists  inflammatory 
leucocytosis  is  also  present,  and  that  he  has  never  been  able  to 
demonstrate  hyperinosis  without  coexisting  increase  in  the  number 
of  leucocytes.  But  leucocytosis  does  not  invariably  imply  hyper- 
inosis, although  the  two  conditions  almost  always  go  hand  in 
hand.  Leucocytosis  may  occur  in  purpura  and  in  malignant 
disease  unattended  by  fibrin  increase;  on  the  other  hand,  in  in- 

1  Zeitschr.  f.  klin.  Med.,  1897,  vol.  xxxiii,  p.  215. 


i3« 


THE  BLOOD  AS  A  WHOLE. 


fluenza  the  fibrin  network  is  denser  than  normal,  while  the  number 
of  leucocytes  is  not  increased. 


VII.  OLIGEMIA. 

The  term  oligemia  signifies  a  reduction  in  the  total  volume  of 
the  blood,  involving  a  diminution  of  both  the  liquid  and  the  cel- 
lular portions.  It  occurs  most  conspicuously  after  hemorrhage, 
and  probably  after  this  accident  only.  Sometimes,  the  hemorrhage 
having  been  profuse,  the  oligemia  proves  rapidly  fatal;  but  in 
other  instances,  where  the  hemorrhage  has  been  less  extensive, 
the  decreased  volume  of  blood  is  slowly  made  up,  first  by  a  rapid 
osmosis  of  serum  into  the  depleted  capillaries  from  the  neighbor- 
ing lymph  spaces,  and  later  by  a  slower  numerical  increase  of 
the  cellular  elements,  the  products  of  an  actual  manufacture  of 
erythrocytes  by  the  blood-making  organs. 

In  some  of  the  advanced  cachectic  states,  in  which  profound 
adynamia  and  poor  nourishment  of  the  body  are  prominent  clin- 
ical manifestations,  there  is  seemingly  good  reason  for  believing 
in  the  existence  of  a  true  oligemia;  but  in  the  absence  of  con- 
firmatory evidence,  reduction  of  the  blood  volume  in  this  class  of 
cases  must  remain  rather  a  suspicion  than  an  accepted  fact.  The 
term  oligemia  is,  therefore,  in  the  light  of  our  present  understand- 
ing, applicable  only  to  blood  losses  resulting  from  hemorrhage. 


VIII.  PLETHORA. 

The  term  plethora  is  currently  used  to  express  a  condition 
characterized  by  an  actual  excess  in  the  total  volume  of  the  blood, 
affecting  both  the  liquid  and  the  cellular  elements.  According 
to  the  views  of  many  of  the  older  and  a  few  of  the  modern  path- 
ologists, a  true  polyemia,  or  an  increase  in  the  blood  volume,  un- 
accompanied by  any  qualitative  changes,  is  thought  to  exist  in 
certain  individuals  whose  mode  of  life  and  luxurious  habits  are 
supposed  to  predispose  and  give  rise  to  excessive  blood-forma- 
tion. The  compatibility  between  a  real  full-bloodedness  and 
a  "high-liver"  was  formerly  much  more  generally  credited  than 
at  the  present  time,  and  the  association  of  such  signs  as  a  rich, 
ruddy  complexion,  enlargement  of  the  superficial  blood  vessels, 
and  a  full,  bounding  pulse  was  depended  upon  for  the  recognition 
of  this  condition.  Of  late,  however,  the  drift  of  opinion  is  against 
the  probability  of  any  such  permanent  increase  in  blood  volume, 
but  until  an  accurate  method  of  estimating  the  total  quantity  of 


HYDREMIA. 


139 


blood  in  the  body  has  been  devised,  the  presence  or  absence  of  a 
real  plethora  must  obviously  remain  conjectural. 

True  plethora  may  occur  as  a  transitory  condition,  as  the  re- 
sult of  the  direct  transfusion  of  blood,  or  the  mechanical  forcing 
back  into  the  general  circulation  of  a  quantity  of  blood  from  a 
part  to  be  removed  from  the  body,  as  by  the  use  of  an  Esmarch 
rubber  bandage  previous  to  the  amputation  of  a  limb ;  in  a  similar 
manner  a  new-born  infant  may  become  temporarily  plethoric  by 
a  complete  emptying  of  the  placenta  before  tying  the  umbilical 
cord.  Plethora  resulting  from  any  of  these  influences  is  invari- 
ably of  a  transient  character,  for  the  physiological  balance  of  the 
organism  rapidly  disposes  of  the  surplus  amount  of  blood  by  de- 
struction of  the  excess  of  cellular  elements  and  by  the  elimination 
of  the  liquid  portions. 

Serous  plethora  may  be  defined  as  an  increase  in  the  volume  of 
blood  due  to  excessive  quantities  of  its  liquid  and  saline  con- 
stituents, without  augmentation  in  the  number  of  its  cellular 
elements.  A  condition  of  this  sort  may  be  dependent  upon  the 
ingestion  of  large  amounts  of  liquids,  upon  the  transfusion  of  saline 
solutions,  or  upon  vasomotor  dilatation,  whereby  the  transfer 
of  an  unduly  large  amount  of  liquids  from  the  tissues  to  the  blood 
vessels  is  promoted.  In  organic  lesions  of  the  kidneys  and  of  the 
heart,  with  diminished  elimination  of  water  from  the  system,  a 
serous  plethora  of  more  or  less  chronicity  may  develop.  The 
condition,  however,  is  usually  of  transient  duration,  as  the  surplus 
liquids  in  the  circulatory  system  are  quickly  disposed  of  and  the 
blood  volume  reduced  to  normal  by  intracapillary  transudation. 
J.  L.  Smith1  believes  that  in  chlorosis  a  true  excess  in  the  volume 
of  blood  exists,  though  Lloyd  Jones2  maintains  that  the  condition  is 
one  of  hydremia  (see  below)  rather  than  of  actual  serous  plethora. 

Cellular  plethora  is  a  term  which  may  appropriately  be  applied 
to  the  condition,  also  known  as  polycythemia,  consisting  in  an  in- 
crease in  excess  of  the  normal  standard  in  the  number  of  erythro- 
cytes. The  circumstances  under  which  this  change  occurs  will 
be  discussed  later.    (See  p.  197.) 


IX.  HYDREMIA. 

A  relative  increase  in  the  quantity  of  the  liquid  constituents  of 
the  blood  is  known  as  hydremia.  This  condition  must  not  be 
confused  with  serous  plethora,  which  is  characterized  by  both  a 
relative  and  an  absolute  increase  in  the  liquids  of  the  blood.  The 

1  Jour.  Physiol.,  1900,  vol.  xxv,  p.  6.  2  "  Chlorosis,"  London,  1897. 


THE  BLOOD  AS  A  WHOLE. 


specific  gravity  of  the  blood  is  observed  to  fall  in  relation  to  the 
degree  to  which  the  change  develops. 

Hydremia  may  be  produced  by  any  factors  which  disturb  the 
normal  relations  between  the  cellular  and  the  liquid  elements  of 
the  blood,  so  that  the  latter  are  unduly  increased.  In  other 
words,  the  blood  is  diluted,  in  consequence  of  which  a  given  drop 
of  such  blood  shows  an  apparent  decrease  in  the  number  of  cel- 
lular elements,  although  the  latter  are  in  reality  unaffected  by  the 
change.  Hydremia  is  observed  after  extensive  hemorrhages,  in 
which  the  primary  effect  of  the  oligemia  is  the  taking  up  by  the 
capillaries  of  an  excess  of  tissue  fluids  to  replace  the  blood  loss; 
later,  as  blood  formation  gradually  makes  up  for  the  cellular  4 
deficiency,  the  normal  ratio  between  the  corpuscles  and  the  plasma 
is  reestablished.  In  the  acute  febrile  injections  hydremia  may 
develop  in  consequence  of  excessive  destruction  of  the  blood 
albumins  by  the  pyrexia.  Hydremia  may  also  occur  as  the  result 
of  the  ingestion  oj  large  amounts  of  liquids,  after  the  injection  oj 
normal  saline  solution,  and  as  a  consequence  of  vasomotor  dila- 
tation. The  watery  constituents  of  the  blood  are  relatively  in- 
creased in  certain  of  the  severe  anemias,  owing  to  the  deficiency  of 
corpuscular  elements,  which  is  compensated  by  fluids  derived  from 
the  tissues.  In  some  dropsical  conditions,  notably  those  associated 
with  renal  and  cardiac  lesions,  hydremia  may  also  be  said  to 
exist,  either  with  or  without  anemia.  Hydremia,  while  it  does  not 
necessarily  imply  the  coexistence  of  anemia,  is  naturally  often  an 
accompaniment  of  the  latter  condition. 

Hydremia  dependent  upon  such  physiological  factors  as  inges- 
tion of  fluids  and  vasomotor  dilatation  is  a  transient  condition, 
for  the  excess  of  fluid  is  promptly  eliminated,  and  the  normal 
relations  restored.  In  other  conditions  the  duration  of  the  change 
obviously  depends  upon  the  nature  and  permanency  of  the  etiolog- 
ical factor  or  factors. 

X.  ANHYDREMIA. 

Anhydremia  is  a  condition  in  which  a  relative  diminution  in 
the  liquid  constituents  of  the  blood  occurs,  as  the  result  of  rapid 
osmosis  from  the  capillaries  into  the  surrounding  tissues.  Inas- 
much as  the  cellular  elements  do  not  share  in  this  draining-away, 
their  number  is  necessarily  increased  in  a  given  drop  of  such  con- 
centrated blood.  The  specific  gravity  of  the  blood  increases  in 
relation  to  the  extent  of  the  fluid  drain. 

Conditions  which  cause  the  sudden  dissipation  of  large  quanti- 
ties of  liquids  from  the  body,  in  consequence  of  hyperactivity  of 


LIPEMIA. 


141 


the  mucous  and  serous  surfaces,  are  the  most  prominent  factors 
in  producing  anhydremia.  Thus,  after  profuse  diarrheas,  urinary 
crises,  free  sweating,  excessive  vomiting,  and  sudden  and  exten- 
sive pleural  and  peritoneal  efjusions  the  blood  becomes  concen- 
trated from  a  temporary  loss  of  its  fluid  elements,  which  pass 
from  the  vessels  into  the  tissues  to  replace  the  liquids  lost  in 
consequence  of  the  drain.  Ewing1  illustrates  this  principle  of 
anhydremia  by  his  observations  on  patients  in  whom  a  pro- 
longed attack  of  malarial  fever  with  severe  anemia  was  followed 
by  enteric  fever  or  by  acute  dysentery.  In  such  instances  the 
thin,  watery  blood  of  the  malarial  infection  promptly  became 
thicker  and  darker  in  color  as  the  inspissating  effects  of  the  com- 
plicating illness  supervened. 

Oliver 2  has  shown  also  that  a  moderate  degree  of  anhydremia 
may  arise  as  the  result  of  various  influences  which  cause  an  in- 
crease in  arterial  tension  and  a  consequent  acceleration  in  the 
transfer  of  water  from  the  vessels  into  the  tissues.  For  example, 
the  change  has  been  brought  about  by  the  influence  of  local  and 
general  exercise,  jaradism,  massage,  cold  bathing,  and  the  admin- 
istration of  suprarenal  extract. 

From  the  nature  of  the  drain,  which  is  rapidly  compensated  by 
the  constant  interchange  which  goes  on  between  the  vessel  and 
the  tissue  fluids,  anhydremia  is  a  temporary  condition.  A  per- 
fect physiological  balance  limits  its  duration  to  brief  periods  of 
time.    (See  "Polycythemia,"  p.  197.) 


XL  LIPEMIA. 

Fat  is  present  in  normal  blood  in  the  form  of  an  exceedingly 
fine  emulsion,  the  amount  varying  in  man  from  1.00  to  3.25  parts 
per  thousand  of  blood,  the  mean  amount  being  1.6,  according  to  the 
analyses  of  Becquerel  and  Rodier.3 

By  the  term  lipemia  is  meant  the  presence  of  an  excess  of  free 
fat  in  the  circulating  blood,  a  phenomenon  which  is  observed  in  a 
number  of  conditions,  both  physiological  and  pathological.  In 
addition  to  fat  globules,  the  blood  in  lipemia  may  also  contain 
fine  granular  particles  failing  to  respond  to  the  usual  tests  for 
fat.  The  nature  of  these  granules  is  still  in  dispute,  but  it  is 
generally  believed  that  they  are  either  a  proteid  substance  pre- 
cipitated in  the  presence  of  free  fat,  or  that  they  represent  the 

1  "  Clinical  Pathology  of  the  Blood,"  2d  ed.,  Philadelphia  and  New  York,  1903. 
2Croonian  Lectures,  Lancet,  1896,  vol.  i,  pp.  1541,  1621,  1699,  and  1778. 
3  Cited  by  Futcher,  Jour.  Amer.  Med.  Assoc.,  1899,  vol.  xxxiii,  p.  1006. 


142 


THE  BLOOD  AS  A  WHOLE. 


albuminous  envelop  surrounding  certain  of  the  fat  globules.1 
During  the  period  of  digestion,  especially  after  a  meal  rich  in 
fats,  the  blood  may  contain  a  sufficient  amount  of  fat  to  give  rise 
to  temporary  lipemia;  the  condition  may  also  be  met  with  in  the 
breast-fed  infant,  in  the  pregnant  woman,  and  in  the  obese. 
Menstrual  suppression  is  also  capable  of  overloading  the  blood 
with  fat. 

The  existence  of  lipemia  is  of  little  clinical  importance,  for  it 
has  been  observed  in  a  number  of  diseases,  so  that  it  cannot  be 
considered  characteristic  of  any  particular  lesion.  It  has  been 
noted  in  the  following  conditions:  arteriosclerosis,  chronic  alcohol- 
ism, diabetes  mellitus,  gout,  certain  diseases  of  the  liver,  heart,  and 
pancreas,  chronic  nephritis,  tuberculosis,  splenitis,  malarial  fever, 
typhus  fever,  Asiatid  cholera,  peritonitis,  pneumonia,  and  poison- 
ing by  phosphorus  and  by  carbon  monoxid.  Lipemia  commonly 
occurs  as  the  result  of  lacerated  wounds  of  the  blood  vessels  situated 
in  fatty  tissues,  and  after  fractures  of  the  long  bones  involving  injury 
of  the  fatty  marrow. 

The  degree  of  lipemia  may  be  so  marked  that  the  macroscop- 
ical  appearance  of  the  fresh  blood  is  altered,  the  presence  of  large 
quantities  of  free  fat  rendering  it  salmon-colored,  turbid,  and 
milky.  This  is  especially  conspicuous  in  the  specimen  of  blood 
serum  obtained  by  centrifugalization,  which  has  a  distinct  grayish, 
opaque  appearance,  not  unlike  that  of  chyle. 

Macroscopically,  the  presence  of  lipemia  may  be  determined 
by  mixing  with  ether  in  a  test-tube  a  portion  of  the  turbid  blood 
serum,  the  excess  of  fat  promptly  dissolving,  so  that  the  serum 
becomes  clear.  Heyl,2  W.  Hale  White,3  and  others  have  been 
able  to  distinguish  lipemic  blood  in  the  retinal  vessels  by  means 
of  the  ophthalmoscope. 

Microscopically,  lipemia  may  be  recognized  by  the  presence 
of  large  numbers  of  glistening  fat  droplets,  about  0.5  to  2  p-  in 
diameter,  which  lie  in  the  plasma  between  the  groups  of  cor- 
puscles, often  exhibiting  very  lively  Brownian  movements.  These 
droplets  respond  to  the  usual  tests  for  fat,  dissolving  in  ether, 
and  staining  black  with  osmic  acid  and  brick-red  with  Sudan  III. 


XII.  MELANEMIA. 

The  occurrence  in  the  circulating  blood  of  minute  particles  of 
melanin  or  pigment,  derived  usually  from  the  hemoglobin  of  the 

1  See  Futcher,  loc.  cit. ;  also  Cole  (cited  by  White),  Lancet,  1903,  vol.  ii,  p. 
1007. 

2  Trans.  Amer.  Ophthal.  Soc,  1880,  p.  54.         3  Lancet,  1903,  vol.  ii,  p.  1007. 


GLYCEMIA. 


143 


erythrocytes  destroyed  by  blood  parasites,  is  known  as  melan- 
emia.  These  melanin  particles  appear  as  fine  bits  of  granu- 
lar matter,  black  or  of  a  reddish-yellow  color,  either  lying  free  in 
the  blood  plasma  or  embedded  in  the  protoplasm  of  the  leuco- 
cytes. In  some  instances  the  granules  are  extremely  small-sized 
and  few  in  number,  and  again  the  amount  may  be  considerable, 
large  numbers  of  pigment  particles  being  apparently  fused  into 
masses. 

Melanemia  is  frequently  present  in  malarial  fever,  especially 
of  the  severer  types,  both  in  the  form  of  free  pigment  and  as 
pigmented  leucocytes.  Particles  of  pigment  in  the  bodies  of  the 
leucocytes  have  also  been  seen  in  cases  of  insolation,  in  relapsing 
fever,  in  melanotic  sarcoma,  and  in  Addison1  s  disease. 

XIII.  GLYCEMIA. 

Glycemia,  or  the  presence  of  grape-sugar  in  the  blood,  occurs 
in  perfectly  normal  blood  to  a  very  slight  degree,  the  quantity  of 
sugar  found  under  physiological  circumstances  not  exceeding  1.5 
parts  per  thousand.1  The  presence  of  sugar  in  excess  of  this  fig- 
ure, which  may  be  termed  hyperglycemia,  is  met  with  in  diabetes 
mellitus,  in  which  disease  as  high  as  9  parts  per  thousand  have 
been  detected.2  The  investigations  of  Freund3  and  of  Trinkler4 
apparently  show  that  the  blood  in  carcinoma,  especially  of  vis- 
ceral involvement,  contains  an  excess  of  some  reducing  agent,  to 
all  intents  and  purposes  identical  with  sugar.  The  former  author, 
in  consequence  of  this  fact,  lays  stress  on  the  finding  as  a  means 
of  differentiating  between  carcinoma  and  sarcoma,  since  no  such 
increase  has  been  observed  as  an  accompaniment  of  the  latter 
type  of  neoplasm.  Lepine5  finds  that  the  sugar  content  of  the 
blood  appreciably  increases  after  extirpation  of  the  pancreas,, 
a  hyperglycemia  developing  within  twenty-four  hours  after  the 
ablation  of  this  organ.  He  also  finds  hyperglycemia  after  liga- 
tion of  the  duct  of  Wirsung.* 

The  most  accurate  method  of  detecting  small  quantities  of 
sugar  in  the  blood  is  by  the  phenylhydrazin  hydrochlorid  test, 
conducted  by  von  Jaksch7  as  follows:  A  small  amount  of  blood, 

1  The  term  "potential  sugar"  (Lepine)  is  applied  to  the  sugar  produced  in 
normal  blood  after  having  been  kept  outside  the  body  for  half  an  hour,  at  a  tem- 
perature of  5 8°  C.  This  sugar  is  believed  to  be  evolved  from  one  or  more  carbo- 
hydrate molecules  of  the  blood  proteids. 

3  Hoppe-Seyler,  Virchow's  Arch.,  1858,  vol.  xiii,  p.  104. 

3  Wien.  med.  Blatter,  1885,  vol.  vii,  pp.  268  and  873. 

4  Centralbl.  f.  d.  med.  Wissensch.,  i8qo,  vol.  xxviii,  p.  498. 

5  Cited  by  Flexner,  Univ.  of  Penna.  Med.  Bull.,  1902,  vol.  xiv,  p.  391. 

8  Sem.  med.,  1903,  vol.  xxiii,  p.  385.     7  Zeitschr.  f.  klin.  Med.,  1886,  vol.  xi,  p.  20. 


144 


THE  BLOOD  AS  A  WHOLE. 


obtained  by  wet-cupping,  is  first  freed  from  proteids  by  adding 
an  equivalent  weight  of  sodium  sulphate  and  then  boiling  and 
filtering,  the  filtrate  thus  obtained  being  used  for  the  test.  A 
solution  is  now  made  in  a  test-tube,  by  mixing  2  parts  of  phenyl- 
hydrazin  hydrochlorid  and  4  parts  of  sodium  acetatl  with  about 
6  c.c.  of  water,  and  gently  heating  the  fluid,  if  necessary,  to 
effect  solution.  Five  c.c.  of  the  proteid-free  filtrate,  while  still 
warm,  are  added  to  an  equal  volume  of  the  test  solution.  This 
mixture  is  then  placed  in  a  test-tube  half  filled  with  water,  heated 
for  half  an  hour  in  a  water-bath,  and  allowed  to  stand  until  cool. 
When  cooling  of  the  mixture  has  occurred,  it  shows  under  the 
microscope  the  presence  of  the  characteristic  yellowish  crystals 
of  phenyl-glucosazon,  either  detached  or  in  clusters,  together  with 
colorless  crystals  of  sodium  sulphate. 


XIV.  URICACIDEMIA. 

The  presence  in  the  blood  of  a  demonstrable  amount  of  uric 
acid  has  been  designated  as  uricacidemia.  The  blood  of  the 
normal  individual  does  not  contain  this  substance  in  amounts 
sufficiently  large  to  be  detected  by  ordinary  clinical  tests,  but  it  is 
found  in  appreciable  quantities  in  a  number  of  pathological  condi- 
tions .  Garrod, 1  many  years  ago,  recognized  that  excessive  accumu- 
lation of  uric  acid  in  the  blood  was  associated  with  gout,  and  he  at- 
tached to  this  sign  much  diagnostic  significance.  Later  investiga- 
tions, however,  have  proved  the  utter  unreliability  of  this  finding 
as  a  pathognomonic  sign  of  this  disease,  for  in  recent  years  a  large 
number  of  other  conditions  has  been  found  to  be  more  or  less 
constantly  accompanied  by  relatively  large  amounts  of  uric  acid 
in  the  circulating  blood.  Notable  examples  of  such  diseases  are 
pneumonia,  hepatic  cirrhosis,  acute  and  chronic  nephritis,  uremia, 
chronic  gastritis,  leukemia,  severe  anemia,  and  those  conditions  in 
which  deficient  blood  aeration  constitutes  a  prominent  clinical 
symptom,  such  as  organic  cardiac  disease,  exudative  pleurisy,  and 
emphysema.  Uric  acid  is  not  found  in  the  blood  in  enteric  fever  nor 
in  rheumatic  fever.  Pyrexia,  of  itself,  evidently  has  no  influence 
in  producing  uricacidemia,  nor  is  it  at  all  probable  that  this  con- 
dition goes  hand  in  hand  with  an  excessive  elimination  of  uric  acid 
in  the  urine. 

Garrod's  test  is  well  adapted  clinically  for  detecting  the  pres- 
ence of  appreciable  quantities  of  uric  acid  in  the  blood.  Slightly 
modified,  it  may  be  applied  in  the  following  manner:  Two 

1  Med.  and  Chirurg.  Trans.,  1854,  vol.  xxxvii,  p.  49;  ihid->  l848>  vol.  xxxi,  p.  183. 


ACETONEMIA  AND  LIPACIDEMIA. 


145 


and  one-half  cc  of  blood  serum,  obtained  by  blistering,  are 
placed  in  a  shallow  watch-glass  and  acidulated  by  the  addi- 
tion of  about  4  drops  of  a  30  per  cent,  aqueous  solution  of  acetic 
acid.  A  linen  thread  is  then  immersed  in  the  acidulated  blood, 
which  is  slowly  evaporated  at  a  temperature  not  exceeding  700 
F.  At  the  expiration  of  from  twenty-four  to  forty-eight  hours, 
if  the  sample  of  blood  contains  uric  acid,  characteristic  crystals 
of  this  substance  are  deposited  upon  the  thread,  their  identity 
being  readily  detected  by  microscopical  examination  and  by  the 
murexid  test. 

XV.  CHOLEMIA. 

The  presence  in  the  blood  of  bile  or  bile-pigments  has  been 
termed  cholemia,  a  condition  which  accompanies  various  forms 
of  icterus.  Bilious  blood  may  have,  as  already  stated,  a  yellow- 
ish-red color,  and  may  yield,  on  agitation,  an  abundant  foam, 
tinged  with  yellow.  Hypertonicity  of  the  serum  and  a  tendency 
toward  hemoglobin  dissociation  are  characteristic  of  cholemic 
blood.  (See  "  Icterus.")  Bilirubin  may  be  detected  in  the  blood 
even  when  urine  tests  for  this  substance  have  proved  negative, 
according  to  von  Jaksch,1  who  employs  this  procedure  to  demon- 
strate its  presence:  About  10  cc.  of  blood,  obtained  by  wet 
cupping,  are  allowed  to  clot,  after  which  the  serum  is  pipetted 
off,  filtered  through  asbestos,  and  coagulated  at  a  temperature  of 
8o°  C.  Thus  treated,  the  presence  of  bilirubin  is  betrayed  by  a 
greenish  discoloration  of  the  serum,  which,  if  bile-free,  remains 
a  pale  straw  color.  Should  a  brownish  color  develop  by  this 
test,  the  presence  of  hemoglobin  in  the  serum  is  indicated. 


XVI.  ACETONEMIA  AND  LIPACIDEMIA. 

The  occurrence  in  the  blood  of  demonstrable  amounts  of  ace- 
tone and  of  fatty  acids  is  referred  to  as  acetonemia  and  lipac- 
idemia^  respectively.  Acetonemia  has  been  found  in  associa- 
tion with  numerous  pathological  conditions,  chiefly  in  those 
characterized  by  pyrexia,  while  fatty  acids  in  the  blood  have  been 
detected  in  diabetic  coma,  in  malignant  jaundice,  in  leukemia, 
and  in  various  acute  injections. 

For  the  recognition  of  acetone  Simon2  recommends  Den- 
ige's  test,  to  be  applied  as  follows:  About  3  cc.  of  blood  are 
treated  with  30  cc  of  Denige's  reagent  (20  gm.  of  concentrated 
sulphuric  acid  mixed  with  100  cc  of  distilled  water,  to  which  5 

1  Loc-  ciL  2  "Clinical  Diagnosis,"  5th  ed.,  Philadelphia,  1004. 

10 


146 


THE  BLOOD  AS  A  WHOLE. 


gm.  of  yellow  oxid  of  mercury  are  then  added),  and  allowed  to 
stand  until  a  dark-brown  precipitate  has  formed,  after  which  the 
supernatant  fluid  is  filtered  off  and  treated  with  more  of  the 
reagent,  so  as  to  effect  complete  precipitation.  It  is  then  acidi- 
fied by  the  addition  of  about  3  c.c.  of  a  30  per  cent,  solution  of 
sulphuric  acid,  and  boiled  for  one  or  two  minutes.  The  appear- 
ance of  a  white  precipitate  on  boiling  indicates  the  presence 
of  acetone.  This  precipitate  may  be  almost  wholly  dissolved 
by  the  addition  of  hydrochloric  acid  in  excess. 

Fatty  acids  may  be  detected  by  boiling  equal  parts,  by  weight, 
of  blood  and  sodium  sulphate,  filtering,  evaporating  the  filtrate 
to  dryness,  and  then  extracting  the  residue  with  absolute  alcohol. 
Microscopical  examination  of  the  residue  will  reveal  crystals  of 
fatty  acids  if  lipac'idemia  exists. 

XVII.  BACTERIEMIA. 

Bacteriemia,  or  the  presence  of  bacteria  in  the 
Occurrence,  circulating  blood,  is  a  condition  associated  with 
a  number  of  infectious  diseases,  in  which  instances 
it  is  frequently,  but  by  no  means  constantly,  possible  to  dis- 
cover the  specific  micro-organism  of  the  disease  in  question  by 
careful  bacteriological  examination  of  the  blood.  The  demon- 
stration in  the  blood  of  such  bacteria  as  pyogenic  cocci  in  gen- 
eral septicemia,  of  the  Streptococcus  pyogenes  and  other  pyogenic 
organisms  in  malignant  endocarditis,  of  the  bacillus  of  Eberth 
in  enteric  fever,  of  the  gonococcus  in  gonorrheal  arthritis,  of 
the  pneumococcus  in  pneumonia,  and  of  the  Bacillus  tuberculosis 
in  severe  cases  of  acute  miliary  tuberculosis,  is  sufficient  proof, 
without  citing  other  instances,  of  the  diagnostic  value  of  bacterio- 
logical blood  examinations.  Such  examinations  are  warranted 
in  every  case  of  severe  infection  the  nature  of  which  appears 
doubtful,  since  by  their  aid  alone  it  is  often  possible  to  derive 
diagnostic  clues  of  the  greatest  practical  value. 

From  the  clinician's  viewpoint,  normal  blood 
Latent      is  absolutely  sterile,  since  no  cultural  method  has 
Infection,    yet  been  devised  by  which  it  is  possible  to  demon- 
strate the  presence  of  bacteria  in  the  circulation 
of  the  healthy  individual.    From  the  pathologist's  standpoint, 
however,  such  a  statement  must  be  accepted  guardedly,  in  the 
light  of  recent  investigations.    Adami,1  in  a  comprehensive  resume 
of  the  whole  field  of  bacterial  infection,  cites  a  series  of  apparently 

1  Jour.  Amer.  Med.  Assoc.,  1899,  vol.  xxxiii,  pp.  1509  and  1572;  also  Ford, 
Jour,  of  Hygiene,  1901,  vol.  i,  p.  277. 


BACTERIEMIA. 


147 


conclusive  experiments  by  his  assistants,  Nicholls  and  Ford,  who 
found  that  the  kidneys  and  livers  of  healthy  animals,  removed 
aseptically  immediately  after  death  and  placed  in  agar-agar  kept 
at  the  temperature  of  the  body,  showed,  after  a  few  days,  a  rela- 
tively abundant  growth  of  bacteria.    This  observer  concludes 
that  under  normal  conditions  the  leucocytes  pass  out  through 
the  mucosa  on  to  the  free  surface  of,  more  especially,  the  alimen- 
tary tract,  some  of  these  cells  then  undergoing  destruction,  while 
others,  now  laden  with  various  foreign  matters,  including  bacteria, 
pass  back  again  into  the  submucosa  and  find  their  way  either 
into  the  lymphatic  channels  or  into  the  portal  venules.    In  both 
of  these  sites  there  exists  a  decided  tendency  toward  bacterial 
disintegration  and  destruction.    Such  isolated  bacteria  as  may 
have  escaped  leucocytal  destruction,  or  removal  by  the  lymphatic 
glands  or  by  the  endothelium  of  the  portal  system,  may  pass 
either  through  the  thoracic  duct  or  through  the  liver,  and  enter 
the  systemic  circulation,  from  which  they  are  eliminated  chiefly 
by  the  kidneys.    Such  a  condition  as  this,  known  as  "latent  in- 
fection" or  "latent  microbism,"  appears  to  be  compatible  with 
perfect  health,  for  the  number  of  bacteria  which  thus  gain  access 
to  the  blood  stream  and  tissues  is  so  small  that  unless  their 
virulence  is  especially  striking  and  the  susceptibility  of  the  indi- 
vidual peculiarly  marked,  the  resisting  powers  of  the  tissues  re- 
main sufficiently  strong  to  prevent  bacterial  proliferation.    It  is 
also  obvious  that  the  presence  in  the  blood  of  so  limited  a  num- 
ber of  bacteria  cannot  be  demonstrated  by  culturing. 

If,  on  the  other  hand,  the  conditions  are  such 
Blood  that  bacteria  multiply  in  the  blood  to  any  decided 
Cultures,  extent,  then  their  development  in  artificial  media 
outside  the  body  may  be  successfully  obtained  in 
many  instances,  provided  that  proper  technic  is  employed.  That 
this  has  not  been  more  successfully  accomplished  is  no  doubt 
due  to  the  powerful  bactericidal  action  of  the  shed  blood,  whereas 
this  influence  in  the  circulating  blood  is  but  trifling.  As  Adami 
remarks,  "Because  certain  observers  have  failed  to  discover 
bacteria  in  the  blood  from  cases  of  infectious  diseases,  it  by  no 
means  follows  that  the  blood  when  shed  has  been  free  from  bac- 
.teria."  In  modern  methods  of  examination  precautions  are 
taken  to  attenuate  the  bactericidal  properties  of  the  shed  blood 
by  freely  diluting  it  with  a  large  quantity  of  fluid  media,  instead 
of  using  relatively  small  amounts  of  solid  culture,  as  has  been 
done  largely  in  the  past,  and  as  the  result  of  this  improved  technic 
blood  culturing  now  yields  a  much  higher  percentage  of  positive 


148 


THE  BLOOD  AS  A  WHOLE. 


findings,  and  gives  more  uniform  results  than  were  formerly 
obtained.    (See  "  Bacteriological  Examination,"  p.  109.) 

Among  the  various  bacteria  which  different 
Bacteria     observers  have  succeeded  in  isolating  from  the 
Found  in     circulating  blood  are  included  many  micro-organ- 
the  Blood,    isms,  the  identity  of  which,  as  etiological  factors 
of  disease,  is  generally  recognized,  and  also  a 
number  to  which  pathogenicity  cannot  be  convincingly  attributed. 
The  following  list  gives  the  most  important  examples  of  the 
former  class: 


B.  aero  genes  capsulatus. 

B.  anthracis. 

B.  coli  communis. 

B.  influenzce. 

B.  lepra. 

B.  mallei. 

B.  cedematis  maligni. 
B.  pestis  bubonicce. 
B.  pneumonice. 
B.  proteus  vulgaris. 


B.  tetani. 

B.  tuberculosis. 

B.  typhosus. 

Diplococcus  intracellular  is  menin- 
gitidis. 
Gonococcus. 

Micrococcus  tetragenus. 
Pneumococcus. 
Pyogenic  staphylococci. 
Pyogenic  streptococci. 


In  addition  to  this  list,  a  certain  amount  of  interest  attaches  to 
the  discovery  in  the  blood  of  certain  bacilli  (Achalme),  micrococci 
(Walker),  and  diplococci  (Triboulet)  in  rheumatic  fever;  of 
peculiar  bacilli  (Afanasiew)  in  relapsing  fever,  in  addition  to  the 
specific  spirillum  of  this  infection;  of  diplobacilli  (Craig)  in 
mumps;  and  of  diplococci  (Class)  in  scarlet  fever  and  in  typhus 
fever  (Balfour  and  Potter).  The  presence  of  the  Bacillus  icte- 
roides  (Sanarelli)  in  the  blood  of  yellow  fever  patients  is  now 
known  to  mirror  a  secondary  infection. 

The  conditions  in  which  the  above-named  bacteria  occur  in  the 
blood  will  be  discussed  in  a  later  section,  under  the  diseases  in 
question.    (See  "  General  Hematology,"  Section  VII.) 


XVIII.  ANEMIA. 

In  a  clinical  sense  the  term  anemia  refers  to 
Definition,  any  deterioration  in  the  quality  of  the  blood,  af- 
fecting the  erythrocytes,  the  hemoglobin,  or 
both  of  these  elements.  Thus,  in  pernicious  anemia  the  most 
conspicuous  deterioration  in  the  quality  of  the  blood  is  a  diminu- 
tion in  the  number  of  erythrocytes,  or  an  oligocythemia;  in  chlo- 
rosis the  most  marked  change  is  usually  a  loss  of  hemoglobin, 


ANEMIA. 


149 


or  an  oligochromemia;  while  in  many  other  anemic  conditions  the 
erythrocytes  and  hemoglobin  are  decreased  more  or  less  propor- 
tionately. While  it  is  true  that,  strictly  speaking,  the  word  anemia 
may  also  be  used  to  designate  a  reduction  in  the  blood  volume, 
this  condition  is  better  defined  by  the  use  of  the  term  oligemia. 
Ischemia  is  a  form  of  local  anemia  resulting  from  some  mechani- 
cal interference  with  the  blood  supply  of  the  affected  area. 

In  certain  individuals  with  such  decided  pallor 
Pseudo-      of  the  skin  and  mucous  membranes  that  their 
anemia.      appearance  at  once  leads  one  to  infer  that  they 
are  suffering  from  a  well-defined  anemia,  no  signs 
of  this  condition  can  be  discovered,  for  even  after  the  most  careful 
examination  of  the  blood  the  number  of  erythrocytes  and  the  per- 
centage of  hemoglobin  may  be  found  to  be  normal.    Such  instances 
of  apparent  blood  deterioration  have  been  called  pseudo -anemia; 
they  are  often  explained  by  hereditary  peculiarities,  by  vaso- 
motor disturbances  affecting  the  superficial  capillaries,  and  by 
deficiencies  in  the  pigment  and  in  the  development  of  the  capillary 
network  of  the  skin.    In  pseudo-chlorosis  the  patient  shows  the 
typical  objective  signs  of  chlorosis,  yet  her  hemoglobin  and  cor- 
puscular values  are  normal.    (See  "  Chlorosis.")  Vermehren1 
has  described,  under  the  term  angiospastic  pseudo -anemia,  the 
transient  periods  of  almost  cadaveric  pallor  which  occur  in  some 
individuals  with  normal  blood,  as  the  result  of  vasomotor  spasm 
provoked  by  cold,  fatigue,  emotion,  and  like  influences.  Dwellers 
in  tropical  countries  are  especially  prone  to  a  spurious  form  of 
anemia,  to  which  the  misnomer  tropical  anemia  is  occasionally 
applied.  Every  medical  clinic  can  furnish  patients  suffering  from 
neurasthenia,  tuberculosis,  and  advanced  Bright's  disease,  whose 
pallid  countenances  are  a  striking  contrast  to  their  normal  blood 
counts.    "Prison  pallor"  suggests  lack  of  fresh  air  and  sunshine 
rather  than  severe  blood  deterioration.  It  does  not  follow,  therefore, 
that  pallor  of  the  skin  and  mucous  membranes  is  invariably  an  indi- 
cation of  anemia,  although  this  sign  is  not  misleading  in  the  ma- 
jority of  instances.    On  the  other  hand,  it  should  not  be  forgotten 
that  persons  of  good  color  and  robust  appearance  sometimes  suf- 
fer from  decided  anemias  without  the  fact  becoming  evident  at 
first  glance.    In  chlorosis  florida,  for  example,  red  cheeks  are  not 
incompatible  with  a  low  hemoglobin  percentage.    In  view  of  these 
sources  of  error,  in  order  to  diagnose  anemia  with  absolute  accu- 
racy, an  examination  of  the  blood  is  essential,  for  no  matter  how 
valuable  other  clinical  signs  may  appear,  the  changes  in  the  blood 
are  often  the  real  key  to  the  situation. 

1  Sem.  med.,  1903,  vol.  xxiii,  p.  167. 


THE  BLOOD  AS  A  WHOLE. 


An  entirely  satisfactory  classification  of  the 
Classifi-      various  forms  of  anemia  still  remains  to  be  de- 
cation.       vised,  in  spite  of  the  numerous  attempts  which 
not  a  few  eminent  authorities  have  made  to 
group  these  conditions  according  to  sound  pathological  consid- 
erations.   Therefore,  largely  for  the  sake  of  convenience,  all 
anemias  may  be  broadly  grouped  into  two  theoretical  classes: 
primary  and  t  secondary. 

According  to  this  tentative  classification,  primary  anemias  may 
be  considered  those  in  which  a  lesion  of  the  hematopoietic  organs 
is  essentially  accountable  for  the  production  of  the  disease.  In 
anemias  of  this  sort,  the  etiological  factors  are  either  entirely  un- 
discoverable,  or,  if  they  are  to  be  detected,  too  trivial  to  explain  the 
intensity  of  the  disease.  Here  the  predominant  clinical  manifesta-. 
tions  are  to  be  found  in  the  changes  occurring  in  the  composition 
of  the  blood,  the  other  symptoms  being  considered  secondary  to, 
and  dependent  upon,  these  alterations. 

Under  the  term  secondary  anemia  are  included  those  cases 
of  anemia  which  are  apparently  secondary  to,  and  symptomatic 
of,  certain  definite  pathological  lesions  not  primarily  affecting 
the  blood-making  organs,  such  as,  for  example,  enteric  fever, 
syphilis,  septicemia,  malignant  disease,  malarial  fever,  and  hemor- 
rhage. In  such  anemias  the  other  clinical  symptoms  are,  as  a 
rule,  much  more  conspicuous  than  the  blood  changes,  which 
are  thought  to  be  secondary.  An  exception  to  this  general  rule 
must  be  taken,  however,  in  regard  to  the  anemia  caused  by  the 
presence  of  the  Bothriocephalus  latus  in  the  intestinal  canal,  for 
in  this  infection  the  blood  picture  is  by  all  odds  the  most  striking 
clinical  manifestation.  It  is,  furthermore,  true,  that  in  some 
instances  a  secondary  anemia  may  apparently  merge  into  one  of 
the  primary  type,  should  the  protracted  duration  of  the  former 
in  course  of  time  cause  such  profound  systemic  effects  that  finally 
the  blood-making  organs  become  exhausted,  and  refuse  ade- 
quately to  supply  the  constant  demand  for  corpuscles,  with  the 
result  that  the  most  prominent  clinical  signs  are  now  found  in 
the  blood,  and  not  in  the  original  symptoms  of  the  disease  in 
question.  The  high  grade  anemia  which  sometimes  follows 
enteric  fever,  becoming  of  such  intensity  that  it  counterfeits  a 
primary  anemia,  may  be  cited  as  an  example  of  this  change. 

Until  further  progress  has  been  made  in  the  study  of  the  physi- 
ology and  pathology  of  the  blood-making  organs  the  following 
provisional  classification  of  the  anemias  may  be  used  for  clinical 
purposes : 

I.  Primary  Anemia. — Chlorosis,  pernicious  anemia,  splenic 


HEMOLYSIS.  151 
1 

anemia,  lymphatic  leukemia,  myelogenous  leukemia,  Hodgkin's 
disease. 

II.  Secondary  Anemia. — Dependent  upon  causes  such  as 
hemorrhage,  intestinal  parasites,  prolonged  lactation,  unjavorable 
hygiene,  metal  poisoning,  malignant  disease,  acute  injections,  and 
chronic  diseases  producing  long-standing  drains  on  the  albumin 
of  the  blood. 

Excluding  the  effects  of  hemorrhage,  deficient 
Pathogenesis,  blood  formation,  excessive  blood  destruction, 
and  a  combination  of  these  two  processes  are 
generally  regarded  as  the  three  possible  essential  factors  in  the  pro- 
duction of  anemia.  Deficient  hemogenesis  is  to  be  attributed  to  a 
large  number  of  different  causes,  among  the  most  prominent  of 
which  may  be  mentioned  the  influence  of  unhygienic  surroundings 
and  insufficient  nourishment  from  improper  food  and  from  in- 
adequate powers  of  assimilation.  It  is  also  probable  that  con- 
genital and  acquired  failure  of  the  blood-making  organs  and  the 
presence  of  growths  which  intercept  the  material  for  blood  forma- 
tion are  to  be  considered  as  the  origin  of  defective  hemogenesis  in 
some  instances.1  Excessive  blood  destruction  may  be  due  to 
acute  febrile  and  infectious  conditions,  or  to  the  presence  in  the 
blood  of  certain  toxins  which  destroy  the  corpuscles.  It  is  char- 
acterized during  life  by  an  excess  of  urobilin  and  iron  in  the  urine, 
and  by  the  development  of  hematogenous  jaundice. 

XIX.  HEMOLYSIS. 

In  order  to  understand  the  process  of  hemol- 
Ehrlich's     ysis  it  is   necessary  briefly  to  refer  to  Ehr- 
Side-chain'    lich's  side-chain  theory  of  immunity,2  the  hy- 
Theory.       pothesis  which  furnishes  the  best  explanation 
of  the  organism's  reaction  against  bacteria, 
toxins,  and  other  noxious  agencies.    According  to  this  theory,  it 
is  assumed  that  the  body  cell  consists  of  a  central  group  of  mole- 
cules by  virtue  of  which  the  inherent  characteristics  of  the  cell  are 
determined  and  maintained,  and  a  second,  subsidiary  molecular 
group,  which,  by  means  of  its  unsatisfied  affinities,  is  capable  of 
combining  with  nutrient  materials,  toxins,  and  other  substances, 
which  are  thus  brought  into  intimate  relationship  with  the  cell 

1  Mackenzie,  Lancet,  1891,  vol.  i,  p.  73. 

2  Proc.  Roy.  Soc,  London,  1900,  vol.  lxvi,  p.  424;  Nothnagel's  "Spec.  Path, 
u.  Ther.,"  1901,  vol.  viii,  p.  1;  Klin.  Jahrb.,  1898,  vol.  vi,  p.  299;  also  Ehr- 
lich  and  Morgenroth,  Berlin,  klin.  Wochenschr.,  1899,  vol.  xxxvi,  pp.  6  and  481; 
ibid.,  1900,  vol.  xxxvii,  pp.  453  and  681;  ibid.,  1901,  vol.  xxxviii,  pp.  251,  569, 
and  598. 


THE  BLOOD  AS  A  WHOLE. 


structure.  These  subsidiary  molecules,  known  as  side-chains  or 
receptors,  are  simply  links  between  assimilable  substances  and  the 
cell,  which  can  neither  be  nourished  nor  poisoned  except  by  the 
intermediation  of  its  receptors.  Just  as  receptors  possess  specific 
affinities  for  linking  with  certain  food  stuffs  and  with  no  others, 
so  there  is  believed  to  be  a  congenial  reaction  between  receptors 
and  toxins,  certain  varieties  of  receptors  combining  with  one  kind 
of  toxin  and  other  varieties  with  another.  The  receptor  and  the 
toxin,  therefore,  must  be  homologous  before  the  two  can  combine. 
The  receptors  concerned  in  the  process  of  toxin  immunity  belong 
to  Ehrlich's  "first  order";  they  have  but  a  single  uniting  bond  for 
combining  with  the  toxin,  and  for  this  reason  are  also  termed 
uniceptors. 


Toxophore. 
Haptophore. 


Body  cell. 

Fig.  41. — Illustrating  the  Mechanism  of  the  Toxin -cell  Union  by  the  Intermedia- 
tion of  Receptors. 

A  toxin  molecule  consists  of  two  atomic  groups,  each  with  dif- 
ferent affinities  and  with  separate  functions.  One,  termed  the 
haptophore  group,  serves  to  combine  the  toxin  unit  with  the  cell 
receptor  for  which  it  has  a  selective  affinity;  the  second,  known  as 
toxophore  group,  serves  to  injure  the  cell  when  the  haptophore- 
receptor  combination  is  formed.  The  mechanism  of  this  anchoring 
of  the  toxin  to  the  vulnerable  cell  may  be  represented  by  the  above 
diagram  (Fig.  41). 

The  union  of  toxin  and  cell  leaves  the  latter  more  or  less  crippled, 
either  so  severely  that  it  dies,  or  but  slightly,  so  that  it  still  lives. 
If  the  latter  be  the  case,  the  cell  commences  to  elaborate  more  re- 
ceptors in  its  combat  against  the  toxin— elaborates  them  in  great 
excess  of  its  needs,  so  that  in  spite  of  the  fact  that  many  of  these 
new-born  receptors  are  promptly  seized  by  other  toxin  molecules, 


HEMOLYSIS. 


153 


some  of  them  are  thrown  off  by  the  cell  and  float  off  free  in  the 
blood  and  other  body  fluids.  These  liberated  receptors,  or  hap- 
tins,  constitute  antitoxin.  In  their  free  state  they  can  combine 
with  homologous  toxin  molecules  just  as  readily  as  when  still  at- 
tached to  the  cell,  and  such  a  combination  obviously  renders  inert 
the  toxin,  since  its  haptophore  group  is  thus  satisfied  and  cannot 
now  become  anchored  to  the  cell.  According  to  Welch's  hypoth- 
esis, these  antidotal  substances  may  act  not  only  in  their  primary 
function  as  toxin  neutralizers,  but,  under  certain  conditions,  may 
irritate  the  invading  bacteria  to  elaborate  similar  substance  for 
their  own  protection.  In  other  words,  this  theory  of  reciprocity 
in  infection  assumes  that  if  bacteria  irritate  the  body  cells,  the  latter 
in  turn  similarly  affect  the  bacteria. 

Toxins  deprived  of  their  toxophore  groups,  but  retaining  their 
haptophore  group,  are  designated  toxoids,  and  such  bodies,  though 
capable  of  becoming  attached  to  the  cells  by  their  haptophore 
group,  are  inert,  because  they  contain  no  toxic  element. 
Toxoids  can  also  unite  with  antitoxin  (free  receptors  or  hap- 
tins)  by  means  of  their  haptophore  link.  Toxins  incompletely 
combined  with  antitoxins,  and  therefore  still  capable  of  causing 
modified  poisonous  effects,  are  known  as  toxones.  The  following 
diagram  illustrates  the  production  of  antitoxin  and  the  union  of 
toxins  and  toxoids  with  the  cell  and  its  liberated  receptors : 


Body  cell. 

P'ig.  42. — Illustrating  the  Elaboration  and  Action  of  Antitoxin. 


The  injection  into  animals  of  bacteria,  various 
Hemolysis,     body  cells,  and  the  products  of  these  substances 
in  time  gives  rise  to  the  development  of  specific 
"antibodies"  in  the  blood  serum  of  the  treated  animal,  as  it  ac- 


*54 


THE  BLOOD  AS  A  WHOLE. 


quires  immunity.  When  the  latter  is  complete,  the  animal's  blood 
will  be  found  to  have  acquired  a  lytic  or  destructive  action  upon 
cells  similar  to  those  injected.  For  example,  the  injection  of  ery- 
throcytes gives  rise  to  hemolytic  serum;  of  bacteria,  to  bacterio- 
lytic serum  for  the  specific  organism  introduced;  of  bone  marrow 
and  lymphatic  tissue,  to  leucolytic  serum;  of  spermatozoa,  hepatic 
cells,  and  epithelial  cells,  to  spermolytic,  hepatolytic,  and  epi- 
theliolytic  sera,  respectively.  The  adaptive  changes  thus  pro- 
duced in  the  animal  injected  are  absolutely  specific — the  injection 
of  erythrocytes  produces  a  serum  acting  only  upon  the  erythro- 
cytes, not  upon  the  leucocytes,  bacteria,  or  body  cells.1 

Isolysis  is  a  term  used  to  denote  a  hemolytic  action  due  to  the 
injection  of  one  animal  with  cells  from  another  animal  of  the  same 
species,  the  active  factors  of  this  process  being  known  as  isolysins. 
The  destructive  influence  of  a  normal  individual's  blood  upon  the 
erythrocytes  of  another  person  illustrates  this  phase  of  hemolysis. 
Autolysis  should  result,  theoretically  at  least,  by  the  immunization 
of  an  animal  against  injections  of  his  own  cells,  with  the  conse- 
quent evolvement  of  substances  termed  autolysins.  The  occurrence 
of  hemolysis  in  icterus,  in  Winckel's  disease,  and  after  internal 
hemorrhage  is  suggestive  of  autolysis. 

The  lytic  property  of  the  blood  Ehrlich  attributes  to  the  inter- 
dependent action  of  two  distinct  elements  of  the  plasma,  the  com- 
bined influences  of  which  are  essential  to  produce  the  change.  In 
the  process  of  hemolysis  the  receptors  of  the  erythrocytes  serve 
to  connect  these  cells,  by  the  interposition  of  an  intermediary 
body,  or  amboceptor,  with  a  complementary  toxic  body,  or  com- 
plement, which,  when  thus  united  to  the  cells,  exerts  its  destructive 
influence.  The  receptors  concerned  in  hemolysis  are  said  to  be- 
long to  the  "  third  order";  they  are  provided  with  two  haptophore 
groups,  one  for  combining  with  the  vulnerable  cell  and  the  other 
with  the  complement,  which  then  can  act  upon  the  cell  attached  to 
the  first  haptophore  group. 

The  amboceptor  is  formed  within  the  body,  as  the  result  of  a 
cellular  hyperactivity  excited  by  the  organism's  adaptation  to 
alien  blood  or  to  other  irritant  and  toxic  material.  Amboceptors 
are  thought  to  represent  liberated  "  third  order"  receptors,  evolved 
and  cast  off  by  the  cells  during  the  process  of  adaptation.  They 
are  stable  substances,  capable  of  progressive  increase,  and  act  as  con- 
necting links  between  the  complement  and  the  cell.    This  function 

1  For  a  complete  account  of  these  reactions  see:  (i)  Vaughan  and  Novy, 
"  Cellular  Toxins,"  Philadelphia,  1902;  (2)  Welch,  Huxley  Lecture,  Lancet,  1902, 
vol.  ii,  p.  977;  (3)  Prudden,  Med.  Rec,  1903,  vol.  lxiii,  p.  241;  (4)  Aschoff,  Zeitschr. 
f.  allg.  Physiol.,  1902,  vol.  i,  p.  69;  (5)  Wassermann,  "  Immune  Sera,"  Eng.  transl. 
by  Chas.  Bolduan,  New  York,  1904. 


HEMOLYSIS. 


155 


of  anchoring  the  complement  to  the  cell  is  performed  by  means  of 
two  groups  of  atoms  (hence  the  term,  amboceptor),  one  with  an 
affinity  for  the  corpuscle  (cytophilic  group),  and  the  other  with 
an  affinity  for  the  complement  (complementophilic  group).  The 
complement,  which  acts  upon  the  erythrocyte  partly  as  an  enzyme 
and  partly  as  a  toxin,  is  normally  present  in  the  blood,  being 
probably  derived  largely  from  the  leucocytes.  It  is  provided 
with  a  haptophore  group  of  atoms,  which  link  it  to  the  ambo- 
ceptor, and  with  a  zymophore  group  (corresponding  to  a  toxin's 
toxophore  group)  upon  the  action  of  which  depends  the  cellular 
destruction.  The  complement  is  of  unstable  nature,  being  de- 
stroyed at  a  temperature  of  550  C,  and  possesses  many  of  the 
characteristics  of  the  enzyme.  Its  toxic  action  upon  the  erythro- 
cytes is  exhibited  only  when  it  is  anchored  to  them  by  the  inter- 
vention of  the  amboceptor,  so  that  unless  this  link  is  formed,  the 
complement  can  exert  no  deleterious  effect  upon  these  cells.  The 
accompanying  diagram  (Fig.  43)  shows  the  mechanism  by  which 
an  erythrocyte  succumbs  to  the  zymotoxic  action  of  the  comple- 
ment: 


Union  of  comple- 
ment, amboceptor, 
and  cell. 


— x  Zymophore. 
—  Haptophore  .J;  i 
Complement. 


Amboceptor. 


Complemento- 

phile. 
Cytophile. 


Erythrocyte. 

Fig.  43. — Illustrating  the  Mechanism  of  Hemolysis. 


Resistance  of  the  erythrocytes  to  hemolysis 
Anti-        is  attributed  to  the  protective  influences  of  sub- 
hemolysis.    stances  known  as  antihemolysins,  which  in  their 
action  correspond  to  antitoxins.  Antihemolysins 
are  formed  within  the  blood  plasma  after  inoculation  with  hem- 
olysins, and  are  of  two  kinds :  anticomplements  and  antiamboceptors. 
The  former  combine  with  the  haptophore  group  of  the  complement, 


156 


THE  BLOOD  AS  A  WHOLE. 


and  the  latter  unite  with  the  cytophilic  group  of  the  amboceptor— 
combinations  which  in  either  instance  break  the  continuity  of  the 
complement-amboceptor-erythrocyte  chain  essential  for  the  cell's 
destruction.  The  action  of  these  two  forms  of  antihemolysins  may 
be  illustrated  thus: 


Erythrocyte. 


Fig.  44. — Illustrating  the  Mechanism  of  Antihemolysis. 
A.  Interference  of  anticomplement  with  complement-amboceptor  union.    B.  Interference  of 
antiamboceptor  with  amboceptor-cell  union.    C.  Antiamboceptor-amboceptor  union.    D.  Anti- 
complement-complement  union. 

Hemolysis,  although  generally  associated  with 
Agglutina-    more  or  less  agglutination  and  precipitation  of  the 
tion  and  Pre-  erythrocytes,  is  not  always  part  and  parcel  of 
cipitation.     these  phenomena.    Serum  may  clump  and  pre- 
cipitate the  cells  without  exerting  the  slightest 
hemolytic  effect,  while,  on  the  other  hand,  dissolution  of  the  cells 
may  progress  without  their  becoming  clumped  or  precipitated. 
The  principles  of  agglutination  and  precipitation  have  been  applied 
clinically  in  the  diagnosis  of  enteric  fever  and  other  specific  in- 
fections, and  in  the  biological  test  for  the  detection  of  human 
blood  (q.  v.). 

The  injection  of  bacteria,  alien  erythrocytes,  and  other  foreign 
cells  produces  in  the  blood  serum  of  the  animal  thus  treated  the 
property  of  agglutinating  and  precipitating,  in  vitro,  the  bacteria  or 
cells  injected.  These  phenomena  are  attributed  to  the  presence, 
in  the  animal's  serum,  of  substances  known  as  agglutinins  and 
precipitins,  developed  during  the  process  of  adaptation  or  im- 


HEMOLYSIS. 


157 


munizalion.  According  to  Ehrlich's  theory,  agglutinins  are 
liberated  receptors  elaborated  by  the  body  cells  concerned  in 
the  process,  such  receptors  having  a  haptophore  group  with  which 
the  bacterium  or  cell,  as  it  may  be,  combines,  and  a  zymophore  or 
agglutinophore  group,  which,  when  this  link  is  formed,  exhibits 
its  clumping  properties.  It  will  be  noted  that  agglutination,  unlike 
hemolysis  and  bacteriolysis,  does  not  involve  the  action  of  a  com- 
plementary toxic  body — the  receptor  at  once  anchors  and  clumps 
the  homologous  cell  or  bacterium  through  the  combined  offices 
of  its  haptophore  and  zymophore  atomic  groups.  Receptors 
of  this  sort  belong  to  Ehrlich's  "second  order."  An  agglutinoid 
is  the  term  used  to  designate  a  receptor  deprived  of  its  zymophore, 
agglutinating  group,  but  retaining  its  haptophore,  combining  group. 
It  is  analogous  to  a  toxoid,  and,  like  this  substance,  is  developed 
by  heat. 

Precipitins  are  elaborated  by  the  injection  of  albuminous 
body  fluids,  such  as  defibrinated  blood,  into  certain  animals  whose 
blood  serum,  in  consequence,  acquires  the  property  of  precipitating, 
in  vitro,  the  albumins  against  which  the  adaptation  is  directed. 
The  serum  of  a  rabbit  adapted  to  human  blood  precipitates  the 
blood  of  man  but  none  other,  except,  in  low  dilutions,  the  blood 
of  certain  monkeys!  (See  p.  117.)  Similarly,  the  injection  of 
milk  from  one  animal  develops  in  the  serum  of  the  animal  treated 
a  precipitin  which  is  specific  for  the  milk  used  in  the  adaptation, 
but  for  milk  of  no  other  species.  "  Antisera,"  as  they  are  termed, 
can  also  be  prepared  for  various  warm-  and  cold-blooded  animals, 
and  such  fluids  precipitate  only  the  blood  of  the  animals  for  which 
adaptation  is  sought,  save  in  the  case  of  closely  related  species, 
in  which  a  partial,  incomplete  reaction  may  occur  in  a  low  dilution. 
Other  albuminous  body  fluids  (pus,  albuminous  urine,  inflam- 
matory exudates,  and  saliva)  are  capable  of  evolving,  after  injec- 
tion, sera  which  precipitate  the  blood  of  the  species  from  which 
they  were  derived.  The  mechanism  of  precipitation  is  analogous 
to  that  of  agglutination,  the  precipitins  consisting  of  liberated 
"second  order"  receptors  provided  with  a  haptophore,  combining 
group,  and  a  zymophore,  precipitating  group  of  atoms  which 
together  act  upon  the  susceptible  cell. 


SECTION  III. 


HEMOGLOBIN,  ERYTHROCYTES,  BLOOD 
PLAQUES,  AND  HEMOKONIA. 


SECTION  III. 


HEMOGLOBIN,    ERYTHROCYTES,    BLOOD  PLAQUES, 
AND  HEMOKONIA. 


I.  HEMOGLOBIN. 

Hemoglobin,  which  occurs  in  the  circulating 
General     blood  in  chemical  union  with  oxygen  as  oxyhem- 

Properties.   oglobin,  is  an  extremely  complex  ferruginous  and 
albuminoid  substance  contained  within  the  stroma 
of  the  erythrocytes.    It  constitutes  approximately  nine-tenths  of 
their  total  bulk,  and  a  trifle  less  than  14  per  cent,  of  the  whole 
blood.    Hemoglobin  displays  a  striking  avidity  for  combining 
with  oxygen  to  form  a  peculiarly  unstable,  but  definite,  chemical 
compound,  and  a  similar  tendency  to  yield  up  to  the  tissues 
much  of  its  oxygen  during  its  passage  through  the  capillary 
circulation.    Under  the  influence  of  deoxidizing  agents  oxyhemo- 
globin may  be  deprived  of  its  loosely  combined  oxygen  molecule, 
the  resulting  oxygen-free  constituent  being  known  as  reduced 
hemoglobin.    Rhombic   crystals   of   oxyhemoglobin,   scarlet  or 
reddish-green  in  color,  are  rapidly  formed  if,  for  any  reason, 
separation  of  this  substance  from  the  corpuscular  stroma  takes 
place.    These  crystals  may  be  easily  demonstrated  by  Reichert's 
method 1  of  laking  a  small  quantity  of  blood  with  ether  and  then 
adding  from  one  to  five  per  cent,  of  ammonium  oxalate.  Met- 
hemoglobin  is  an  oxygen  compound  of  hemoglobin  containing  the 
same  quantity  of  combined  oxygen  as  the  latter,  but  differing  from 
it  m  holding  its  oxygen  constituent  in  a  more  intimate  union. 
The  dingy  brown  color  which  develops  in  a  solution  of  oxyhemo- 
globin after  prolonged  exposure  to  the  atmosphere  evidences  the 
production  of  this  variety  of  blood  pigment.    (See  "  Methemo- 
globinemia," p.  167.) 

The  amount  of  iron  (in  the  form  of  hemochromo gen)  which 
hemoglobin  contains  is  considerable— somewhat  in  excess  of 
four  per  cent.    It  has  been  shown,  clinically,  by  estimates  made 
with  the  ferrometer  and  the  hemometer,  that  no  fixed  parallelism 
1  Amer.  Jour.  Physiol.,  1903,  vol.  ix,  p.  97. 
11  161 


1 62       ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 


is  maintained  between  the  percentage  of  hemoglobin  and  the  iron 
contained  in  the  blood.1 

Under  the  action  of  acids,  strong  alkalis,  or  heat,  hemoglobin 
may  be  readily  decomposed  into  two  constituents:  hematin,  or 
an  iron-containing  principle;  and  an  albuminous  residue  of  un- 
known character,  but  somewhat  resembling  globulin.  In  combi- 
nation with  hydrochloric  acid  hematin  forms  a  crystalline  hydro- 
chlorid  of  hematin  termed  hemin,  or  Tekhmanrts  crystals.  Under 
the  microscope  these  crystals  appear  as  black  or  dark  brown, 
elongated,  rhombic  prisms  belonging  to  the  triclinic  system,  which 
are  insoluble  in  water,  alcohol,  ether,  chloroform,  and  dilute 
acids.  They  may  be  demonstrated  by  preparing  a  slide  of  blood 
(or  of  any  dried  substance  containing  blood  pigment)  to  which  a 
small  quantity  of  common  salt  has  been  added;  a  drop  of  glacial 
acetic  acid  is  then  run  beneath  the  cover-glass,  so  that  it  mixes 
with  the  blood  and  salt,  and  the  specimen  thus  prepared  is  heated 
to  just  below  the  boiling  point  over  a  Bunsen  flame.  On  cooling, 
Teichmann's  crystals  may  be  seen  under  the  microscope  with  a 
low-power  dry  objective.    (See  p.  116.) 

Iron-free  hematin,  or  hemato porphyrin,  may  be  derived  from 
blood  by  the  admixture  of  concentrated  sulphuric  acid.  This 
substance  is  closely  related  chemically  to  urobilin,  and  occurs  oc- 
casionally as  a  pigment  in  nature  and  in  normal  and  pathological 
urines.  Hematoidin,  which  is  also  free  from  iron,  occurs  m  the 
form  of  reddish,  rhombohedral  crystals,  only  in  old  clots  resulting 
from  blood  extravasations,  such  as  cerebral  hemorrhages  and 
splenic  infarcts.  It  is  derived  from  hematin,  and  is  probably 
identical  with  bilirubin.  .  . 

The  chief  source  of  hemoglobin  is  the  iron 

Origin.  contained  in  various  food  products,  about  10 
mgm.  daily  representing  the  amount  of  this 
metal  ingested  in  an  ordinary  diet,  according  to  the  analyses 
of  Stockman.2  In  the  event  of  a  stoppage  of  this  source  of  an 
iron  supply,  the  formation  of  hemoglobin  may  proceed  from  the 
supply  of  iron  stored  up  in  the  various  organs  of  the  body,  notably 
in  the  liver.  Bunge  3  has  shown  that  in  the  young  infant,  whose 
natural  food,  milk,  contains  but  a  slight  trace  of  iron,  this  source 
•of  hemoglobin  manufacture  is  most  potent. 

The  recent  experiments  of  Aporti 4  regarding  the  origin  ot 
hemoglobin  and  the  erythrocytes  have  shown  that  animals  sub- 

1  Rosin  and  Jellinek,  Zeitschr.  f.  klin.  Med.,  1900,  vol.  xxxix,  p.  109. 

2  Jour.  Physiol.,  1897,  vol.  xxi,  p.  55;  ibid.,  1895,  vol.  xvm,  p.  484- 

3  Zeitschr.  f.  physiol.  Chem.,  1892,  vol.  xvi,  p.  177. 

4  Centralbl.  f.  inn.  Med.,  1900,  vol.  xxi,  p.  41- 


HEMOGLOBIN. 


163 


jected  to  repeated  bleedings  and  kept  on  an  iron-free  diet  are  able, 
up  to  a  certain  point,  to  utilize  the  supply  of  body  iron  for  hemo- 
globin manufacture;  but  that  when  such  a  demand  became  so 
great  that  this  supply  was  exhausted,  the  red  corpuscles  became 
progressively  paler  and  paler,  and  the  animal  finally  died.  During 
the  course  of  these  experiments,  if  the  animal  received  injections 
of  iron,  a  prompt  and  striking  increase  in  hemoglobin  occurred, 
the  gain  ranging  from  50  to  95  per  cent,  within  a  week's  time! 
The  injection  of  arsenic,  on  the  contrary,  produced  no  effect  upon 
the  hemoglobin  percentage,  although  it  caused  an  increase  in  the 
number  of  erythrocytes.    The  investigations  of  Stockman  and 
Charteris1  show  that  arsenic  does  not  stimulate  hemogenesis  in 
the  bone  marrow,  and  that  its  favorable  action  in  malarial  fever 
and  diseases  of  this  class  is  probably  due  to  its  parasiticidal  effect. 
In  animals  injected  with  small  doses  of  arsenic  the  marrow  changes 
consisted  of  hyperemia,  decrease  in  the  number  of  giant  cells  and 
fat  cells,  increase  in  the  leucoblasts,  and  slight,  if  any,  prolifera- 
tion of  erythroblasts. 

Baumann,2  studying  the  effects  of  iron  carbonate,  iron  albumin- 
ate, and  arsenic  upon  regeneration  of  the  blood  in  dogs  after  hem- 
orrhage, arrived  at  these  conclusions:  that  the  administration  of 
either  Blaud's  pill  or  an  albuminate  of  iron  causes  a  rapid  gain  in 
hemoglobin,  even  to  a  higher  figure  than  that  originally  found 
before  the  blood  loss,  the  effects  of  each  of  these  preparations  of 
iron  being  similar;  that  arsenic  and  iron  combined,  although 
stimulating  hemoglobin  formation  less  than  the  above  drugs, 
are  better  general  hemogenetic  agents,  so  far  as  regeneration  of 
the  corpuscles,  proteids,  and  plasma  is  concerned;  and  that 
arsenic,  when  given  alone,  is  but  an  indifferent  blood-builder. 
The  practical  import  of  these  experiments  is  patent. 

Diminution  in  the  amount  of  hemoglobin,  as 
Variations    indicated  by  the  hemometer,  is  known  as  oligo- 
in  Amount,    chromemia,  or  achroiocythemia.    It  is  a  condition 
usually,  but  not  invariably,  associated  with  a  cor- 
responding decrease  in  the  number  of  erythrocytes.     An  ap- 
parent increase  in  the  hemoglobin  percentage  may  result  from  the 
concentration  of  the  blood  caused  by  a  reduction  in  the  quantity 
of  blood  plasma  consequent  to  excessive  drains  upon  the  liquids 
of  the  body.     By  a  similar  physical  mechanism  factors  produc- 
ing a  dilution  of  the  blood  are  capable  of  causing  an  apparent 
diminution  m  the  hemoglobin.    Marked  oligochromemia  is  com- 
monly observed  in  chlorosis,  pernicious  anemia,  and  leukemia; 

1  Jour.  Path,  and  Bacteriol.,  1903,  vol.  viii,  p.  443. 
Jour.  Physiol.,  1903,  vol.  xxix,  p.  18. 


1 64      ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 

and  in  the  secondary  anemias  dependent  upon  such  factors  as 
hemorrhage,  mineral  poisoning,  acute  and  chronic  infections, 
malignant  neoplasms,  and  constitutional  diseases.  The  behavior 
of  the  hemoglobin  under  such  conditions  is  more  fully  alluded  to 
in  connection  with  the  lesions  in  question.  Poggi,1  from  a  series 
of  experiments  upon  normal  women,  has  shown  that  the  hemo- 
globin is  slightly  lowered  (10  or  15  per  cent.)  for  a  few  days  before 
menstruation,  but  with  the  establishment  of  the  flow  the  ohgo- 
chromemia  soon  disappears.  The  primary  loss  he  attributes  to 
retarded  hemogenesis  consequent  to  the  lessened  consumption  of 
albumin  occurring  in  menstruating  women,  while  the  subsequent 
gain  he  explains  by  the  increased  functional  activity  of  the  hemato- 
poietic organs.  Double  oophorectomy  in  sexually  active  bitches 
is  followed  by  a  distinct  oligochromemia  and  by  a  less  marked 
oligocythemia,  persisting  for  from  two  to  six  weeks,  but  m  old 
dogs  the  operation  has  no  such  effect.  This  experimental  evi- 
dence is  advanced  by  Breuer  and  von  Seiller2  in  corroboration 
of  the  ovarian  theory  of  chlorosis. 

In  passing,  it  may  be  of  interest  to  compare  the  degree  of 
hemoglobin  loss  in  the  various  forms  of  anemia,  as  illustrated  by 
the  following  averages  determined  by  the  writer : 

Average  of  50  estimates  in  pernicious  anemia  25.5  per ^  cent. 

"       "  "       "        "  chlorosis  43-2 

«       "  "       "  leukemia  39-4 

"       "  "       "        "  secondary  anemia  55-2 

Bierfreund's  investigations3  in  Mikulicz's  clinic  have  led  to  the 
current  impression  among  surgeons  that  it  is  highly  dangerous  to 
give  a  general  anesthetic  to  a  patient  whose  hemoglobin  percent- 
age is  below  30;  some  operators  regard  40  per  cent,  as  the 
lowest  limit  of  safety,  and  refuse  to  employ  any  but  a  local  anes- 
thetic in  cases  with  an  oligochromemia  exceeding  this  figure, 
except  under  circumstances  of  imperative  necessity.  Any  one, 
however,  who  has  attempted  to  verify  the  correctness  of  this  gen- 
eral belief  must  accept  it  with  a  shrug  of  the  shoulders.  The 
writer  knows  of  numerous  patients  whose  hemoglobin  percentages 
all  were  below  30  in  whom  operations  under  general  anesthesia  with 
ether  were  followed  by  uneventful  recovery;  in  one  instance  (a 
pan-hysterectomy  lasting  more  than  an  hour  and  a  half)  the 
hemoglobin  was  but  21  per  cent.,  yet  no  ill  effects  were  observed. 

Patients  with  hemoglobin  percentages  of  from  15  to  30  have 

1  Policlin.  Roma,  1899,  vol.  vi,  p.  1. 

2  Wien.  klin.  Wochenschr.,  1903,  vol.  xvi,  p.  869. 

3  Langenbeck's  Arch.,  1890-91,  vol.  xli,  p.  1. 


HEMOGLOBIN.  1 65 

been  successfully  operated  by  Girvin,  Shober,  Le  Conte,  Noble, 
Baldy,  J.  C.  Da  Costa  and  others.1 

Assuming  that  in  the  normal  adult  14  gm. 
Absolute     represent  the  average  amount  of  hemoglobin  in 
Amount.      100  gm.  of   blood,  the  absolute    amount  of 
hemoglobin  may  be  readily  calculated  thus: 

Hemoglobin  percentage  X  14      100  =  Grams  of  hemoglobin    in   100  gm.  of 

blood. 

For  example,  in  blood  in  which  the  percentage  of  hemoglobin, 
as  determined  by  the.hemometer,  is  found  to  be  40,  the  calcula- 
tion (40  X  0.14)  gives  the  absolute  amount  of  hemoglobin  as 
5.6  gm. 

The  proportionate  amount  of  hemoglobin  con- 
Color        tained  in  each  erythrocyte,  or  its  corpuscular 
Index.        richness  in  hemoglobin,  is  known  as  the  color 
index,  or  blood  quotient,  or  valeur  globulaire. 
In  normal  blood  the  color  index  is  theoretically  expressed  by  the 
figure  1,  although,  practically,  it  varies  from  0.95  to  1.05  in  men, 
and  from  0.9  to  1  in  women.2 

In  those  anemias  in  which  the  decrease  in  the  amount  of 
hemoglobin  in  the  blood  is  coincident  with  a  proportionate  de- 
crease in  the  number  of  erythrocytes,  the  color  index  remains 
practically  at  the  normal  figure.  If,  however,  the  cellular  de- 
crease happens  to  be  relatively  greater  than  the  hemoglobin 
loss,  then  the^  index  will  naturally  be  found  to  rise  above  normal; 
thus,  in  pernicious  anemia,  in  which  condition  the  loss  of  cells 
is  proportionately  much  greater  than  the  loss  of  hemoglobin, 
high  color  indices,  approaching  or  even  exceeding  1.25,  are  fre- 
quently observed.  On  the  contrary,  if  the  hemoglobin  loss  is  rela- 
tively more  excessive  than  the  corpuscular  decrease,  the  color 
index  falls  below  normal;  for  example,  in  chlorosis,  in  which,  as 
a  rule,  the  decrease  affects  the  hemoglobin  much  more  strikingly 
than  the  erythrocytes,  low  indices,  such  as  0.50  or  less,  are  common. 

To  calculate  the  color  index,  the  percentage  of  hemoglobin  is 
divided  by  the  percentage  of  erythrocytes,  the  result  being  ex- 
pressed in  decimals.  In  order  to  simplify  this  procedure  5,000,- 
000  erythrocytes  per  c.mm.  must  be  arbitrarily  considered  as 
normal,  or  100  per  cent.  To  obtain  the  percentage  of  cor- 
puscles the  actual  number  counted  in  one  c.mm.  of  blood  is 
simply  multiplied  by  two,  and  two  or  three  decimals  pointed  off 
from  the  left,  depending  upon  whether  the  count  is  below  or 

1  Trans  Coll  of  Phys.  of  Phila.  (Sect,  on  Gynecology),  1902,  vol.  viii,  p.  26; 
also  Amer.  Jour.  Obstet.,  1902,  vol.  xlv,  pp.  666  and  701 
Oliver,  loc.  cit. 


1 66       ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 

above  the  normal  5,000,000.    The  following  examples  serve  to 
illustrate  the  calculation  in  several  conditions : 
Normal  Adult. 

Erythrocytes:  5,000,000  per  c. mm.  (100  per  cent.). 

Hemoglobin:  100  per  cent. 

100      100  =  1 :  Color  index. 
Secondary  Anemia. 

Erythrocytes:  2,650,000  per  c.mm.  (53  per  cent). 

Hemoglobin:  40  per  cent. 

40  -f-  53  =  0.75:  Color  index. 
Pernicious  Anemia. 

Erythrocytes:  840,000  per  c.mm.  (16.8  per  cent.). 

Hemoglobin:  18  per  cent. 

18  -T-  16.8  =  1.07:  Color  index. 
Chlorosis. 

Erythrocytes:  4,100,000  per  c.mm.  (82  per  cent.). 

Hemoglobin:  32  per  cent. 

32  -4-  82  =  0.39:  Color  index. 
These  examples,  of  course,  refer  only  to  the  usual  blood  find- 
ings, for  the  color  index  is  by  no  means  always  high  in  pernicious 
anemia,  nor  always  low  in  chlorosis.  The  color  index  shows 
simply  the  relative  relations  of  the  hemoglobin  and  the  corpus- 
cular percentages.  It  is  only  suggestive,  not  diagnostic,  of  a 
specific  blood  disease. 

The  term  hemoglobinemia  is  used  to  designate 
Hemoglo-      a  condition  in  which  the  hemoglobin  is  dissolved 
binemia.       from  the  corpuscular  stroma  as  the  result  ^  of 
some  pathological  factor,  and  is  held  in  solution 
by  the  blood  plasma.    In  extreme  instances  this  condition  is 
sooner  or  later  succeeded  by  hemoglobinuria. 

Among  the  most  potent  causal  factors  of  hemoglobinemia  are 
certain  drugs  which  act  as  blood  poisons  when  administered  in 
toxic  doses,  of  which  the  following  are  examples:  arseniuretted 
hydrogen,  sulphuretted  hydrogen,  potassium  chlorate,  carbolic  acid, 
hydrochloric  acid,  sulphuric  acid,  pyrogallic  acid,  nitrobenzol,  anti- 
mony sulphid,  iodin,  naphthol,  and  many  of  the  coal-tar  deriva- 
tives, such  as  acetanilid,  antipyrin,  and  phenacetin.  A  similar 
liberation  of  the  hemoglobin  may  be  observed  as  the  result  of 
poisoning  by  certain  varieties  of  mushrooms,  by  some  snake- 
venoms,  by  the  bite  of  scorpions,  and  by  a  number  of  vegetable 
glucosids.  Sunstroke,  extensive  burns,  and  exposure  to  excessive 
cold  are  also  capable  of  giving  rise  to  hemoglobinemia.  Experi- 
mentally, hemoglobinemia  may  be  produced  by  the  transjuston 
of  blood  from  one  animal  into  the  circulation  of  another  belonging 
to  a  different  species. 


HEMOGLOBIN. 


167 


Hemoglobinemia  is  observed  with  more  or  less  constancy  in  a 
number  of  acute  infectious  diseases,  such  as  grave  cases  of  septice- 
mia, diphtheria,  malignant  jaundice,  syphilis,  malarial  fever,  enteric 
fever,  scarlet  fever,  yellow  fever,  typhus  fever,  and  variola.  It  also 
may  occur  in  scurvy  and  in  Raynaud's  disease,  and  is  a  prominent 
blood  finding  in  those  two  obscure  conditions  known  as  epidemic 
hemoglobinuria  of  the  new-born  and  paroxysmal  hemoglobinuria. 

Hemoglobinemia  may  be  readily  detected  by  the  following 
method,  recommended  by  von  Jaksch : 1  A  small  amount  of  blood, 
drawn  from  the  patient  by  means  of  a  cupping-glass,  is  imme- 
diately placed  in  a  refrigerator,  in  which  it  is  allowed  to  remain 
for  twenty-four  hours.  In  normal  blood  the  serum  which  separates 
at  the  expiration  of  this  period  is  of  a  perfectly  clear  straw-color, 
whereas  if  hemoglobinemia  exists,  the  serum  is  colored  a  beautiful 
ruby-red.  If  this  hemoglobinemic  serum  is  examined  with  the 
spectroscope,  the  two  characteristic  absorption  bands  of  oxy- 
hemoglobin may  be  observed.  If  it  is  coagulated  by  heat,  a 
deep  brown  color  is  imparted  to  the  coagulum. 

Methemoglobinemia,  or  the  presence  in  the 
Methemoglo-  circulating  erythrocytes  of  methemoglobin,  is 

binemia.  produced  by  the  action  of  a  number  of  toxic 
substances,  which,  if  given  in  sufficiently  massive 
doses,  may  seriously  or  fatally  cripple  the  oxygenating  functions 
of  the  blood.  Among  the  agencies  which  cause  this  conversion 
of  oxyhemoglobin  into  methemoglobin  are  potassium  chlorate, 
anilin,  iodin,  bromin,  ether,  turpentine,  acetanilid,  potassium  per- 
manganate, hydrochinon,1  kairin,  thallin,  and  pyrocatechin.  The 
inhalation  of  amy  I  nitrite  and  the  intravenous  injection  of  sodium 
nitrite  also  act  in  a  similar  manner.  Henri  and  Mayer2  found  that 
methemoglobinemia  could  be  produced  by  the  influence  of  radium 
rays. 

Spectroscopical  examination  of  the  blood  is  essential  for  the 
detection  of  methemoglobinemia.  The  spectrum  of  methemo- 
globin in  alkaline  solution  shows  three  absorption  bands:  one 
well-marked  band  between  C  and  D  of  Fraunhofer's  lines  and 
two  others  of  much  less  distinct  appearance,  lying  between  D 
and  E,  each  immediately  adjacent  to  the  lines.  In  acid  and  neu- 
tral solutions  the  spectrum  of  methemoglobin  shows  four  absorp- 
tion bands :  a  decided  one  between  C  and  D,  two  between  D  and 
E,  and  one  closely  adjacent  to  F.  This  spectrum,  it  is  true,  is 
identical  with  that  produced  by  an  acid  solution  of  hematin,  but 
it  may  be  easily  distinguished  from  the  latter  by  the  fact  that 

1  "Clinical  Diagnosis,"  3d  ed.,  London,  1807,  p.  75. 

2  Sem.  med.,  1904,  vol.  xxiv,  p.  68. 


1 68       ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 

the  spectrum  of  methemoglobin,  when  acted  upon  by  ammonium 
sulphid,  changes  first  to  that  of  oxyhemoglobin,  and  later  to 
that  of  reduced  hemoglobin,  while  when  hematin  is  thus  treated, 
a  spectrum  which  shows  two  bands  between  D  and  E  is  pro- 
duced. 

Aside  from  the  bright,  cherry-red  color  of  the 
Carbon  Mon-  blood  in  coal-gas  poisoning  the  presence  of  car- 
oxid  Hemo-    bon  monoxid  hemoglobin  may  be  determined  by 
globin.       spectroscopical  examination  and  by  a  number  of 
distinctive  chemical  reactions. 
Recalling  the  characteristic  spectrum  of  oxyhemoglobin  (two 
distinct  absorption  bands  between  D  and  E,  the  one  nearest  D 


D 


5  b 


Oxyhemoglobin. 


Methemoglobin. 


Reduced  Hemo- 
globin. 


CO  Hemoglobin. 


1 

1 

ap 

n 

H 

SI 

mm 

fit 

| 

Fig.  45. — Principal  Blood  Spectra. 


being  darker,  narrower,  and  more  sharply  defined),  it  is  found  that 
in  the  spectrum  of  carbon  monoxid  hemoglobin  these  bands 
are  replaced  by  two  others,  also  between  D  and  E,  but  nearer 
together,  and  somewhat  closer  to  the  violet  end  of  the  spectrum. 
This  distinction,  which  may  be  so  slight  as  to  appear  confusing, 
is  at  once  emphasized  by  the  fact  that  the  addition  of  ammo- 
nium sulphid  has  absolutely  no  effect  upon  the  carbon  mon- 
oxid spectrum,  while  it  transforms  the  spectrum  of  oxyhemoglo- 
bin into  that  of  reduced  hemoglobin. 

Carbon  monoxid  hemoglobin  in  the  blood  is  also  demonstra- 


THE  ERYTHROCYTES. 


169 


ble  by  the  following  simple  lest  devised  by  Hoppe-Seyler 1 :  A 
small  quantity  of  blood,  removed  from  the  patient  by  means  of 
a  wet-cup,  is  mixed  with  twice  its  volume  of  a  10  per  cent,  solu- 
tion of  potassium  hydrate.  Thus  treated,  blood  containing  car- 
bon monoxid  hemoglobin  changes  the  color  of  the  mixture  to  a 
rich  cinnabar-red,  while  with  normal  blood  the  solution  turns 
brownish-green. 


II.  THE  ERYTHROCYTES. 

The  erythrocytes  or  red  corpuscles  are  thin, 
Appearance    flattened,  biconcave  discs,  of  sharply  defined, 
in  regular  outline  and  of  smooth,  even  surface. 

Fresh  Blood.  That  they  are  neither  bell-shaped  nor  globular, 
as  is  also  maintained,  is  obvious  on  careful 
microscopical  examination.  In  the  blood  of  the  normal  indi- 
vidual the  erythrocyte  does  not  possess  a  nucleus.  When  the 
corpuscle  is  examined  microscopically  as  it  rests  upon  its  flat  sur- 
face, its  central  concavity  is  plainly  indicated  by  a  dark  central 
area  surrounded  by  a  narrower,  lighter  rim  as  the  periphery  of  the 
cell  is  brought  into  sharp  focus,  changing  to  a  pale,  white  center 
encircled  by  a  darker  periphery  as  the  objective  is  brought  closer 
to  the  corpuscle.  When  viewed  in  profile,  it  is  shaped  somewhat 
like  a  slim  dumb-bell,  with  regularly  rounded  poles  tapering 
from  either  end  toward  a  shallow  central  concavity  on  either 
surface.  The  color  of  the  cells,  when  examined  singly  under  the 
microscope,  is  a  pale  greenish-yellow,  but  when  they  are  col- 
lected in  masses,  a  more  or  less  marked  reddish  tint  becomes  ap- 
parent. The  erythrocytes  possess  a  peculiar  tendency  of  collect- 
ing and  adhering  in  more  or  less  regularly  arranged  piles,  like 
rolls  of  coins  stacked  up  face  to  face,  this  being  known  as  rouleaux 
formation. 

After  withdrawal  of  the  blood  from  the  body  various  structural 
changes  in  the  erythrocytes,  commonly  known  as  crenation,  may 
be  observed.  In  normal  blood  the  rapidity  with  which  these 
changes  progress  depends  upon  the  quantity  of  air  which  leaks 
in  between  the  slide  and  the  cover-glass,  and  thus  causes  de- 
generation of  the  corpuscular  stroma.  The  development  of  one 
or  more  small,  bright,  highly  refractive  spots  in  the  body  of  the 
corpuscle,  and  a  slight  indentation  of  the  cell's  periphery  are  the 
the  most  conspicuous  indications  of  beginning  crenation.  As  the 
process  goes  on,  more  and  more  of  these  hyaline  points  develop, 

1  Loc.  cit. 


170      ERYTHROCYTES,   BLOOD  PLAQUES,   AND  HEMOKONIA. 

until  finally  the  whole  surface  of  the  corpuscle  becomes  thickly 
studded  with  glistening,  bead-like  spines.  As  the  stroma  be- 
comes drier  and  drier,  its  typical  biconcavity  and  sharply-cut  out- 
line are  lost,  contracting  strands  of  the  stroma  are  seen  to  extend 
from  point  to  point  among  the  beaded  projections,  the  periphery 
of  the  cell  changes  to  a  cogged  rim,  and  finally  the  cell  becomes 
shrunken  and  shriveled  up  into  a  small,  many-starred  asterisk. 
Some  of  the  erythrocytes  become  fragmented,  and  small  bits  of 
their  stroma  are  observed  to  break  off  and  float  through  the  plasma. 
Others  become  progressively  paler  and  paler  as  the  hemoglobin 
is  dissolved  out,  until  complete  decoloration  occurs.  Still  others 
become  distorted  into  designs  of  every  conceivable  shape,  so 
that  their  resemblance  to  the  normal  cell  becomes  most  remote. 
These  changes,  which  never  occur  in  normal  blood  until  the  cells 
have  been  exposed  to  prolonged  atmospheric  influence,  must 
not  be  confused  with  similar  alterations  in  the  structure  of  the 
erythrocytes  occurring  as  the  result  of  pathological  states  of  the 
blood.  The  latter  changes  are  described  more  fully  in  another 
place.    (See  p.  184.) 

The  finer  structure  of  the  erythrocyte  is  still 
Histological  a  moot  point  among  different  histologists,  the 
Structure,  view  most  generally  accepted  regarding  it  as  a 
homogeneous  cell  composed  of  an  insoluble 
spongy  network,  the  stroma  0}  Rollet,  in  the  interstices  or  trabec- 
ular of  which  is  embedded  a  soluble,  finely  granular  substance, 
the  hemoglobin,  existing  probably  as  a  compound  with  some  un- 
known constituent  of  the  cell.  In  lieu  of  a  distinct  limiting 
membrane  the  portions  of  the  stroma  nearest  to  the  surface  of 
the  corpuscle  are  condensed,  to  protect  it  from  injury  during  its 
movement  through  the  blood  stream.  This  outer  layer,  accord- 
ing to  Peskind,1  is  composed  of  a  proteid  substance,  lecithin, 
and  cholesterin,  but  contains  no  hemoglobin.  The  corpuscles  are 
highly  elastic  and  contractile,  to  permit  of  the  rapid  and  marked 
temporary  distortions  of  shape  which  they  constantly  undergo  in 
the  circulating  blood. 

Other  authorities,  notably  Schafer,2  disagree  with  Rollet's  view, 
inclining  rather  to  consider  the  erythrocytes  as  vesicular  masses, 
consisting  of  an  external  envelop  inclosing  a  fluid  contents. 
Thus,  Schafer  believes  that  the  cell  consists  of  two  distinct  por- 
tions, a  colored  and  a  colorless,  the  former  being  a  solution  of 
hemoglobin,  while  the  latter,  or  so-called  stroma,  consists  chiefly 
of  lecithin  and  cholesterin,  together  with  a  small  amount  of  cell 

1  Amer.  Jour.  Physiol.,  1903,  vol.  viii,  p.  404. 

2  Quain's  "Anatomy,"  Philadelphia,  1891,  pt.  2,  p.  210. 


THE  ERYTHROCYTES. 


171 


globulin.  Without  attempting  to  discuss  the  correctness  of  either 
of  these  two  views,  a  single  tangible  reason  for  regarding  the 
corpuscle  according  to  Rollet's  opinion  may  be  stated,  viz.:  the 
fact  that  exposure  of  blood  to  destructive  temperatures  results  in 
fragmentation  of  the  corpuscles  into  numerous  minute  portions, 
each  one  of  which  consists  of  a  bit  of  hemoglobin-containing 
stroma.  This  obviously  seems  to  disprove  the  existence  of  a 
limiting  membrane,  without  further  investigation. 

In  the  human  body  an  active  manufacture  of 
Origin  and    erythrocytes  constantly  goes  on  during  health, 
Life  History,  in   order   to  compensate   for  the  continuous 
drain  on  their  number  by  the  destruction  of  those 
cells  which  have  become  incapable  of  function  and  useless,  their 
life  cycle  being  run.    That  this  reproduction  is  the  direct  answer 
to  a  call  for  new  cells  is  proved  by  the  prompt  and  rapid  increase 
of  corpuscles  following  the  loss  of  blood  from  hemorrhage.  That 
such  a  manufacture  is  attempted  in  severe  pathological  conditions, 
although  the  attempts  are  sometimes  abortive,  is  evinced  by  the 
large  numbers  of  immature  and  misshapen  erythrocytes  which 
appear  in  the  blood  in  certain  of  the  grave  anemias. 

In  the  adult  it  is  generally  conceded  that  the  erythrocytes 
are  reproduced  in  the  red  bone  marrow,  being  developed  from 
their  direct  antecedents,  the  nucleated  erythrocytes  or  erythro- 
blasts,  which  exist  in  this  tissue  in  large  numbers.  The  erythro- 
blasts  appear  to  multiply  in  the  thin-walled  capillaries  and  veins 
of  the  red  marrow,  and,  having  lost  their  nuclei,  become  trans- 
formed into  normally  developed  erythrocytes,  which  pass  from  the 
blood  channels  of  the  marrow  into  the  general  circulation.  Some 
authorities  have  attributed  to  the  spleen  and  lymphatic  glands  a 
share  in  the  formation  of  the  red  cells,  while  others  have  main- 
tained that  they  may  be  transformed  from  the  leucocytes  in  the 
circulating  blood,  but  none  of  these  theories  has  been  associated 
with  convincing  evidence,  so  that  it  is  fair  to  consider  the  red 
bone  marrow  the  chief,  if  not  the  only,  seat  of  production,  in 
the  light  of  our  present  knowledge  of  the  subject.  Hayem's 
ingenious  theory,  that  the  erythrocytes  arise  from  the  hematoblasts, 
does  not  enjoy  the  confidence  of  modern  investigators. 

When  finally  the  erythrocyte,  after  having  executed  its  function 
for  a  certain  length  of  time,  becomes  useless  in  its  primary  office 
as  an  oxygen  carrier,  its  death  ensues,  the  destruction  of  the 
cell  probably  taking  place  largely  in  the  liver  and  to  a  less  degree 
in  the  spleen.  Bain1  has  shown  that  this  hemolytic  power  re- 
sides in  both  of  these  viscera,  the  liver  acting  chiefly  upon  the 

1  Jour.  Physiol.,  1903,  vol.  xxix,  p.  352. 


172       ERYTHROCYTES,   BLOOD  PLAQUES,   AND  HEMOKONIA. 


erythrocytes  and  the  spleen  affecting  mainly  the  leucocytes. 
After  the  passage  of  blood  through  the  liver  it  was  proved  that 
the  hemoglobin-deficient  cells  were  most  prone  to  destruction, 
that  the  hemoglobin  content  of  the  invulnerable  cells  was  dis- 
tinctly increased,  and  that  the  perfusion  appreciably  augmented 
the  quantity  of  iron  in  the  liver  and  was  accompanied  by  a  consid- 
erable output  of  highly  pigmented  bile.  The  perfused  spleen  was 
also  found  to  contain  an  increase  in  the  amount  of  iron,  indicative 
of  a  relatively  slighter  destruction  of  erythrocytes.  Splenectomy 
in  animals  does  not  to  any  great  extent  interfere  with  erythro- 
cytic destruction  (Lapicque).1  Warthin's  2  studies  show  that  de- 
struction of  the  erythrocytes  also  occurs  in  the  splenolymph 
glands,  minute  vascular  sinuses  situated  chiefly  in  the  retroperi- 
toneal and  mediastinal  tissues,  and  in  the  thyroid  and  thymus 
regions.  The  possibility  that  certain  of  the  partly  degenerate 
cells  also  undergo  a  certain  form  of  repair,  first  in  the  spleen  and 
then  in  the  liver,  rendering  them  still  capable  of  function,  is  an 
interesting  but  obviously  unproved  conjecture. 

The  average  diameter  of  the  erythrocyte  is 
Size.  about  7.5  fi,3  its  average  thickness  being  about 
1.8  fi.  According  to  Gram,4  the  diameter  appears 
to  vary  somewhat  with  the  geographical  and  climatic  conditions 
surrounding  the  individual,  being  considerably  larger  in  inhabi- 
tants of  northern  countries  than  in  southerners,  as  the  following 
average  measurements  of  this  observer  attest : 

Country.  Average  Diameter. 

!taly   7  to  7.5  fi 

France   7.5  to  7.6 

Germany   7.8  ju 

Norway   8-5/" 


Hayem5  distinguishes  three  different  sizes:  large,  averaging 
8.5//  in  diameter;  medium,  averaging  7.5  fx  in  diameter;  and 
small,  averaging  6.5/^  in  diameter.  Of  these  three  classes,  ap- 
proximately 75  per  cent,  are  of  the  medium  size,  while  12.5  per 
cent,  each  are  large  and  small.  The  diameter  varies  within  some- 
what wider  limits  in  the  infant  and  in  the  young  child  than  in  the 
adult.  It  is,  however,  not  materially  influenced  by  sex.  The 
pathological  increase  and  decrease  in  the  diameter  of  the  erythro- 
cytes occurring  in  certain  anemias  are  discussed  in  another  place. 

1  Med.  News,  1903,  vol.  lxxxii,  p.  311. 

2  Jour.  Boston  Soc.  Med.  Sci.,  1901,  vol.  v,  p.  414. 

■  The  Greek  letter  n  is  used  to  represent  a  micromillimeter,  or  T^  of  a 
millimeter,  which  is  a  standard  unit  of  measurement  used  in  microscopy. 

4  Fortschr.  d.  Med.,  1884,  vol.  ii,  p.  33.  5  Loc.  cit. 


THE  ERYTHROCYTES. 


173 


The  normal  number  of  erythrocytes  in  the 
Normal  healthy  male  adult  may  be  approximated  at 
Number.     5,000,000  to  the  c.mm.  of  blood.    Higher  counts 

than  this  are  frequently  observed,  however, 
especially  in  healthy,  well-developed  men,  so  that  this  figure 
should  be  taken  to  represent  a  rather  low  average,  subject  to  an 
upward  fluctuation  of  half  a  million  cells,  and  occasionally  even 
more.  In  females  a  count  of  about  4,500,000  erythrocytes  per 
c.mm.  may  be  regarded  as  normal. 

Arterial  and  venous  blood  contain  practically  the  same  number 
of  corpuscles,  the  apparent  slight  increase  in  favor  of  the  latter, 
mentioned  by  some  observers,  being  within  the  limits  of  technical 
error.  For  a  like  reason,  under  normal  conditions,  peripheral 
blood  may  be  taken  as  representative  of  the  blood  of  the  entire 
body.  Blood  derived  from  dependent  parts  of  the  body  contains 
a  diminished  proportion  of  corpuscular  elements.  Oliver's1 
studies  of  this  question  have  shown  that  blood  from  the  finger 
invariably  gives  a  higher  count  of  erythrocytes  than  blood  from 
the  toe,  this  disparity  being  explained  by  the  fact  that  the  larger 
quantity  of  lymph  gravitating  to  the  more  dependent  parts  of  the 
body  causes  a  dilution  of  the  blood  in  these  areas. 

This  term  has  been  applied  by  Capps 2  to  the 
Volume       figure  representing  the  percentage  volume  of  the 
Index.        individual  erythrocyte,  in  contradistinction  to  the 

color  index,  which  expresses  the  amount  of  hemo- 
globin in  the  single  cell.  It  is  calculated  by  dividing  the  percent- 
age volume  of  the  erythrocytes  as  a  whole,  obtained  by  centrifu- 
galization  of  the  blood,  by  the  percentage  number  of  erythrocytes, 
as  determined  by  the  actual  count  with  the  hemocytometer,  the 
normal  volume  index  being  taken  as  1.00.  For  example,  the 
erythrocyte  column,  after  centrifugalization  with  the  hematokrit, 
reaches  to  the  mark  40  on  the  capillary  tube,  indicating  a  total 
volume  of  80  per  cent.;  while  the  count  with  the  hemocytometer 
gives  3,000,000  cells  per  c.mm.,  or  60  per  cent,  of  the  normal  num- 
ber. Then,  80-^60,  or  1.33,  equals  the  volume  index,  a  figure 
which  in  this  instance  shows  an  increase  of  33  per  cent,  in  the 
volume  of  each  corpuscle.  As  a  general  rule,  it  may  be  stated  that 
the  volume  index  and  the  color  index  rise  and  fall  together, 
although  the  parallelism  between  the  two  is  not  always  closely 
maintained.  The  volume  index  is  generally  lowered  in  chlorosis, 
in  leukemia,  and  in  most  of  the  secondary  anemias,  while  in 
pernicious  anemia  it  tends  to  rise  above  the  normal  standard. 

1  hoc.  cit. 

2  Jour.  Amer.  Med.  Assoc.,  1900,  vol.  xxxvi,  p.  464;  also  Jour.  Med.  Re- 
search, 1903,  vol.  v,  p.  367. 


174       ERYTHROCYTES,   BLOOD  PLAQUES,   AND  HEMOKONIA. 


The  cell's  volume  is  influenced  mainly  by  factors  affecting  cell 
degeneration,  and  is  altered  but  slightly  by  osmotic  influences. 
During  blood  regeneration  the  volume  of  the  cell  is  restored  before 
the  color  becomes  normal.  . 


III.  INFLUENCE  OF  PHYSIOLOGICAL  FACTORS  ON 
THE  ERYTHROCYTES. 

Polycythemia,  associated  with  a  proportion- 
Age  and  Sex.  ately  high  percentage  of  hemoglobin,  is  found 
in  the  blood  of  the  new-born  infant  immediately 
after  birth,  the  maximum  counts  being  observed  some  time  during 
the  first  twenty-four  hours  of  life,  after  which  period  they  progres- 
sively diminish  until,  at  the  end  of  eight  or  ten  days,  about 
1,000,000  cells  per  c.mm.  have  been  lost.  Each  period  of  nursing 
is  generally  followed  by  a  prompt  temporary  decrease  in  the 
count,  and  a  similar  change  has  been  observed  as  the  effect  of 
premature  ligation  of  the  cord  at  birth.  Hayem1  found  an  aver- 
age of  5,368,000  erythrocytes  per  c.mm.  in  17  infants  at  birth, 
the  highest  count  being  6,262,000,  and  the  lowest,  4,340,000. 
Fehrsen2  regards  6,000,000  per  c.mm.  as  the  average  count  at 
birth.  The  cause  of  this  polycythemia  is  attributed  to  concentra- 
tion of  the  blood  from  the  abstraction  of  water  by  the  tissues  to 
replace  the  fluids  of  the  body  lost  during  the  first  few  days  of  life. 
As  soon  as  this  loss  is  made  up  by  the  ingestion  of  a  sufficient 
amount  of  liquids  by  the  child,  the  normal  relation  between  the 
liquid  and  the  solid  portions  of  the  blood  is  reestablished,  so 
that  the  polycythemia  disappears. 

During  the  growth  of  the  adult  the  average  number  of  erythro- 
cytes continues  to  rise,  until  the  maximum  number  is  attained  at 
some  time  between  the  third  and  fifth  decades,  after  which  a  de- 
crease is  observed,  usually  becoming  more  marked  as  the  decline 
of  life  progresses.  Schwinge3  and  others  have  shown  that  during 
the  period  of  sexual  activity  the  counts  in  females  are  generally 
lower  than  in  males,  but  that  after  the  climacteric  the  number  of 
cells  in  the  two  sexes  is  practically  identical. 

The  influence  of  age  and  sex  upon  the  number  of  erythrocytes 
is  well  illustrated  in  the  following  table  prepared  by  Sorensen4 : 

Age.                                    Males.  Age.  Females. 

5  to  8  days   5,769,500  1  to  14  days  5,560,800 

5  years  4,950,000  2  to  20  years  5,120,000 

19.5  to  22  years   5,600,000  15  to  28  years  4,820,000 

25  to  30  years  5,340,000  41  to  61  years  5,010,000 

50  to  52  years  5,137,000 

82  years  4,174,700 

1  Loc.  cit.  2  Jour.  Physiol.,  1903,  vol.  xxx,  p.  322. 

3  Pfltiger's  Arch.,  1898,  vol.  Ixxiii,  p.  299.  4  Cited  by  von  Limbeck,  loc.  cit. 


INFLUENCE  OF  PHYSIOLOGICAL  FACTORS. 


!75 


There  are  no  conspicuous  changes  in  the  num- 
Pregnancy,    ber  of  erythrocytes  in  any  of  these  conditions. 
Menstruation,  In  primiparae  there  is  often  a  slight  decrease  in 
and  the  number  of  corpuscles,  particularly  in  the  later 

Lactation,  months  of  pregnancy,  but  in  multiparae  this 
change  is  rarely  observed.  Distinct  anemia  dur- 
ing gestation  is  invariably  pathological,  although  a  moderate  de- 
gree of  hydremia  may  be  physiological.  J.  Henderson1  found 
an  average  hemoglobin  percentage  of  68.2  in  38  cases  at  term, 
and  an  average  erythrocyte  count  of  3,975,348;  by  the  eleventh 
day  after  delivery  these  values  increased  to  74  and  4,020,000, 
respectively.  Postpartum  oligocythemia  commonly  develops,  the 
intensity  of  which  depends  largely  upon  the  amount  of  blood 
lost  and  upon  the  general  health  of  the  woman;  this  loss  of  cells 
is  gradually  made  up,  and  unless  convalescence  is  delayed,  reaches 
the  normal  by  the  second  or  third  week  after  delivery.  Bar  and 
Daunay  2  have  determined  that  the  density  of  the  blood  progres- 
sively declines  toward  the  end  of  pregnancy,  but  rapidly  increases 
after  delivery. 

During  menstruation  there  may  be  a  trifling  reduction,  caused 
by  the  physiological  hemorrhage  of  the  phenomenon,  but  the 
loss  is  rapidly  made  up  in  a  few  days'  time.  Sfameni3  found  that 
a  transient  polycythemia  usually  occurs  shortly  before  the  estab- 
lishment of  the  menstrual  flow,  and  that  the  average  loss  of  hemo- 
globin and  corpuscles  during  the  flow  does  not  exceed  4.5  per  cent., 
the  decrease  being  in  direct  proportion  to  the  actual  volume  of 
blood  lost. 

In  healthy,  robust  women  lactation  is  accompanied  by  a 
normal  count,  but  in  weak,  young  girl-mothers,  particularly 
those  of  the  "chlorotic  age,"  a  moderate  reduction  is  sometimes 
observed. 

Here  maybe  noted  O.  Schaffer's  observation,4  thus  far  uncon- 
firmed, that  pregnancy  can  be  detected  by  an  increased  affinity 
of  the  erythrocytes  for  iodin  in  blood  obtained  by  puncture  of  the 
cervix.  Using  a  reagent  containing  1  gm.  of  iodin,  2  gm.  of  potas- 
sium iodid,  and  300  c.c.  of  water,  Schaffer  found  that  the  number 
of  iodin-stained  erythrocytes  began  to  increase  immediately  after 
conception,  until  just  before  delivery  they  became  at  least  twenty 
times  more  numerous  than  the  unstained  cells,  which  in  the  non- 
pregnant woman  they  outnumber  only  between  two  and  five  to  one. 

1  Amer.  Jour.  Obstet.,  1902,  vol.  xlv,  p.  745. 

2  Sem.  med.,  1904,  vol.  xxiv,  p.  28. 

3  Centralbl.  f.  Gynakol.,  1899,  vol.  xxiii,  p.  131 1. 

4  Ibid.,  1901,  vol.  xxv,  p.  1375. 


176       ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 

Well-developed,  robust  individuals  average  a 
Constitution  larger  percentage  of  erythrocytes  than  the  poorly 
and  nourished  and  weakly.    In  the  former,  counts 

Nutrition,  much  in  excess  of  5,000,000,  and  in  the  latter 
counts  of  less  than  5,000,000,  are  the  rule. 
Fasting,  inasmuch  as  it  causes  a  drain  upon  the  liquid  elements 
of  the  vascular  system,  may  rapidly  bring  about  an  apparent 
polycythemia  due  to  concentration  of  the  blood,  this  increase  m 
cells  being  in  direct  relation  to  the  length  of  abstinence  from  food. 
Hayem1  states  that  a  twenty-four  hours'  fast  will  cause  a  gain  of 
between  400,000  and  500,000  cells;  while  the  experiments  of  Reyne 
on  a  dog,  starved  to  death  after  a  twenty-four  days'  fast,  showed 
an  increase  of  2,500,000  corpuscles  at  the  expiration  of  this  period. 

•'  Active  muscular  exercise  (gymnasium  work, 
Muscular    walking,  running,  swimming,  and  so  forth)  pro- 
Exercise.     vokes  transient  increase  in  the  peripheral  eryth- 
rocyte count,  due  primarily  to  increased  blood 
pressure,  which  not  only  inspissates  the  blood,  but  also  disseminates 
peripherally  many  cells  which  hitherto  lay  inactive  m  the  deeper 
circulation.    From  the  studies  of  Willebrand3  and  of  Zuntz  and 
Schumberg4  it  seems  that  the  duration  of  this  increase  stands  m 
inverse  ratio  to  the  length  of  the  period  of  exercise.  Hawke 
found  that  the  average  gain  in  erythrocytes  was  21  per  cent,  alter 
swimming,  16.6  per  cent,  after  sprinting,  12.8  per  cent,  after  walk- 
ing, and  12  per  cent,  after  bicycling. 
&  Physical  labor  prolonged  to  the  point  of  fatigue 

Fatigue.  appreciably  diminishes  the  number  of  erythro- 
cytes. Cadet's6  investigations  of  the  blood  of  a 
number  of  peasants,  examined  after  two  months  of  hard  field 
labor  during  the  summer,  showed  a  moderate  oligocythemia— m 
one  instance  a  loss  of  over  1,000,000  cells,  and  in  the  others  dimi- 
nutions averaging  about  one-half  of  this  figure.  Cadet  believes 
that  this  anemia  is  referable  to  a  true  blood  destruction,  and  notes 
as  a  rather  mythical  support  of  this  view  that  the  blood  plaques 
were  increased  in  these  cases. 

Among  other  factors  increasing  the  erythrocyte  count  may  be 
noted  cold  tubbing  (Winternitz  ;7  Thayer*),  warm  baths  (Knopf el- 
macher9),  and  general  massage  (J.  K.  Mitchell10). 

,  T  2  Cited  by  Hayem,  loc.  ext. 

3  Skandin.  Arch.  f.  Physiol.,  1903,  vol.  xiv,  p.  176. 

4  "  Studien  zu  einer  Physiologie  des  Marsches,'  Berlin,  1901. 

5  Amer  Tour.  Physiol.,  1904,  vol.  x,  p.  384. 

•  Cited  by  Hayem,  loc.  cit.        7  Centralbl.  f.  klin.  Med.,  1893,  vol.  xiv,  p.  i77- 

8  Johns  Hopkins  Hosp.  Bull.,  1893,  vol.  iv,  p.  37- 

9  Wien.  klin.  Wochenschr.,  1893,  vol.  vi,  p.  810. 

10  \mer.  Jour.  Med.  Sci.,  1894,  vol.  cvii,  p.  502. 


INFLUENCE  OF  PHYSIOLOGICAL  FACTORS.  177 

Within  an  hour  after  a  meal  there  is  a  slight 
Digestion,    transitory  increase  in  the  number  of  erythro- 
Food.        cytes,  amounting  on  the  average  to  a  gain  of  one- 
quarter  of  a  million  cells  to  the  c.mm.  This  acme 
is  soon  followed  by  a  gradual  decline,  corresponding  to  the  period 
ot  digestion,  the  normal  standard  being  regained  within  two  or 
three  hours  after  the  preliminary  rise  began.   Corresponding  fluc- 
tuations m  the  hemoglobin  and  in  the  density  of  the  blood  also 
occur. 

.  Oliver 1  states  that  these  variations  are  not  affected  by  the  taking 
of  liquids  with  meals,  for  he  has.  noticed  that  they  were  quite 
as  pronounced  when  water  was  withheld.  The  same  observer  has 
shown-  that  these  fluctuations  correspond  accurately  to  what  he 
terms  the  "digestive  lymph  wave,"  or  the  to-and-fro  intermediary 
circulation  between  the  capillaries  and  the  lymph  spaces  excited  by 
the  ingestion  of  food.  Immediately  after  a  meal  this  wave  begins 
to  rise,  and  comcidentally  with  this  leakage  of  fluid  from  the  blood 
into  the  tissues  the  hemoglobin  and  erythrocyte  values  begin  to 
rise,  as  the  blood  thus  becomes  more  and  more  concentrated  The 
acme  is  reached  within  an  hour,  and  at  this  time  the  blood  count 
and  the  percentage  of  lymph  in  the  tissues  are  at  their  maximum. 
Hie  wave^  then  begins  to  decline  slowly,  and  as  the  effused  fluid 
gradually  is  restored  to  the  blood  vessels,  the  hemoglobin  and  cor- 
puscle figures  correspondingly  decline,  until  they  reach  normal, 
alter  the  lapse  of  two  or  three  hours  after  their  initial  rise  The 
following  table,  from  von  Limbeck,3  illustrates  the  variations  in  the 
red  and  white  cells  caused  by  taking  food. 

Time.  Erythrocytes.        Leucocytes.  Hemoglobin. 

lllI5^M'  f       5'5%°°°  7,666  98  per  cent. 

12  m.    Dinner  of  meat  and  farinaceous  food. 

12:15  P.M.  5,320,000  6,166 

1  =  15  P-  m.  5,480,000  8,500 

2  :  x5  p-  m.  4,733,ooo  12,000 

V-Hl'  ™  4,872,000  I4,ooo  89  per  cent. 

4  •  15  P-  M.  4,720,000  10,830 

Hayem 4  believes  that  meat  eaters  average  a  higher  percentage  of 
erythrocytes  than  vegetarians,  on  account  of  the  more  nitrogenous 
character  of  their  food,  and  that  a  diet  of  fats  and  albuminoids  is 
most  favorable  for  the  increase  of  the  cellular  elements  of  the 
blood. 

1  Loc.  cit.  2  t        i.  1  ■• 

3  L(?c_  ciL  Lancet,  1903,  vol.  11,  p.  940. 

Loc.  cit. 


I78      ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 

The  habitual  polycythemia  of  individuals  liv- 
High        ing  in  high  altitudes  is  an  interesting  and  inade- 
Altitodes.    quatcly  explained  fact  in  hematology.  Viault, 
Wolff  and  Koeppe,2  Egger,3  and  other  observers 
have  shown  the  invariable  occurrence  of  this  polycythemia  both 
rnTnhabkants  of  elevated  districts  and  in  the  occasional  vrsrtor. 
In  the  case  of  the  latter,  as  the  individual  ascends  from  the  sea- 
level  to  the  mountainous  district,  a  rapid  increase  m  corpusc  es 
and  in  hemoglobin  develops,  this  increase  bearing  a  certain  re a- 
tion  to  the  height  ascended,  and  becoming  apparent  usually 
within  twenty-four  or  forty-eight  hours  after  his  arrival  in  the 
highland.    Campbell  and  Hoagland*  computed  the  increase  at 
Sf  rate  of  50,000  cells  to  the  c.mm.  per  1000  feet  of  elevation. 
Ten  hours'  stay  in  a  balloon,  at  a  height  of  over  1 5,000  feet,  pro- 
duced no  morphological  changes  in  the  blood  of  two  aeronaut 
Schroetter  and  Zuntz,5  who  undertook  this  experiment •  Viault 
counted  8,000,000  erythrocytes  to  the  c.mm.  in  the  residents  of  the 
SfflU  at  an  elevation  of  above  t^sea-fcvd, 

Cazeauxc  found  7,100,000,  at  a  height  of  5904  feet,  tgger 
counted  7,oo=,ooo  at  Arosa,  at  a  height  of  6100  feet;  and  Wolff 
and  Koeppe  found  an  average  of  5,97°,°°°  in  dwellers  at  Reibolds- 
grhn,  at  a  height  of  2257  feet-  ©liver'  relates  the  interesting  ex- 
perience of  finding  in  his  own  blood,  during  a  stay  at  Davos  Plate, 
a!  an  elevation  of  5200  feet,  an  increase  of  corpuscles  within 

^^S^^^T  ^e  fact  that  the 
higher  the  altitude  the  higher  is  the  count  of  erythrocytes. 


Height  above 

Place. 

Sea-level. 

0 

148  meters. 

■  -    3J4  " 

--    425  " 

700 

1,800 

The  Cordilleras. . 

--4>392 

Count  of 

Erythrocytes.  Author. 

4,974,000  Laache. 

5,225,000  Schafer. 

5^322,000  Reinert. 

5,752,000  Stierlin. 

5,748,000  Koeppe. 

5,900,000  Koeppe. 

7,000,000  Egger. 

8,000,000  Viault. 


1  Compt.  rend.  Soc.  biol.,  Paris,  1890  vol.  m,  p.  9*7- 

2  Munch,  med.  Wochenschr.,  1893,  vol.  xl,  p.  9°4- 

3  XII  Cong.  f.  inn.  Med.,  Wiesbaden,  1893. 

*  Amer.  Jour.  Med.  Sci.,  1901,  vol.  cxxn,  p.  654. 

Phbf  Z. 3cU°l  X'  P'  l82'    8  "LeSons  de  Clinique  Medicate,"  Paris,  xSg6,  p.  237 


INFLUENCE  OF  PHYSIOLOGICAL  FACTORS. 


179 


Foa  reports  that  animals  taken  to  a  height  of  10,000  feet 
develop  polycythemia  within  eight  hours  after  their  arrival,  and 
that  the  increase  disappears  within  thirty-six  hours  after  their 
return  to  a  normal  level.  On  the  contrary,  Armand-Delille  and 
Meyer  were  unable  to  detect  any  definite  changes  either  in  the 
peripheral  and  heart  blood  or  in  the  hematopoietic  organs  of  ani- 
mals kept  for  from  two  to  seven  weeks  at  an  altitude  of  6000  feet. 

The  hemoglobin  changes  which  accompany  these  cellular 
alterations  are  never  so  marked  as  the  latter,  both  the  rise  and 
the  fall  being  less  rapid;  consequently  it  is  common  to  find  a  low 
color  index  at  first,  whereas  later,  inasmuch  as  the  rapidity  of 
the  cellular  loss  is  greater  than  the  fall  in  hemoglobin,  a  high 
color  index  is  likely  to  persist  for  some  time  after  return  to  the  low- 
land.   Curry3  could  determine  no  consistent  changes  in  hemo- 
globin, the  volume  of  the  cells,  or  the  specific  gravity  of  the  whole 
blood  at  an  elevation  of  6000  feet.  The  blood  changes,  as  a  rule,  are 
more  conspicuous  in  normal  than  in  anemic  persons.    In  phthisics 
hvmg  in  high  altitudes,  Meissner  and  Schroder4  found  that  the 
hemoglobin  value  rose  and  fell  in  relation  to  the  patient's  im- 
provement and  decline  in  health.    Kemp5  calls  attention  to  the 
fact  that  the  morning  erythrocyte  count  is  always  higher  by  from 
500,000  to  1,000,000  than  the  evening  estimate.    He  also  noted 
that  a  large  increase  in  the  number  of  blood  plaques  developed 
as  the  patient  ascended  to  a  high  elevation. 

_  Concentration  of  the  blood  doubtless  explains  the  polycythe- 
mia of  high  altitudes,  this  change  being  due  largely  to  the  great 
loss  of  body  fluids  (Grawitz),  and  partly  to  the  increased  arterial 
tension  (Oliver)  arising  from  a  rarefied  atmosphere.  Koeppe's 
ingenious  theory  that  the  process  mirrors  an  actual  manufacture 
of  new  cells  is  scarcely  tenable,  for  although  this  observer  has 
tound  numerous  microcytes  and  poikilocytes  coincidentally  with 
the  appearance  of  the  polycythemia,  normoblasts  were  not  de- 
tected, as  an  evidence  of  rapid  hemogenesis,  nor  did  such  signs 
of  excessive  blood  destruction  as  icterus  and  hemoglobinuria  de- 
velop, as  the  increased  count  rapidly  declined  on  the  individual's 
descent  to  a  lower  level. 

It  has  been  recently  urged  that  in  high  elevations  the  effect 
upon  the  hemocytometer  of  atmospheric  pressure  and  tempera- 
ture may  be  the  real  secret  of  the  cellular  increase,  but  how  such 
influences  act,  if,  indeed,  they  are  active,  is  unknown. 

*  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  1097. 

«  fowf^  T3'  V?^Xm',p-  -37?-  3  Amer-  Med"  *<*>*>  voL  iv,  p.  367. 

•  £  n      7    m  °f  TVS1°  °glCal  Twenties,"  Phila.,  1903,  vol.  x,  ^191 . 
vol  x^  p  r77WS'  I9°4'        ™'  P-  383 ;  alS°  J°hnS  H°Pkins  Hosp.  Bull.,  1904, 


l8o      ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 

A  sea  climate  apparently  causes  a  moderate 
Climate.      increase  in  the  number  and  hemoglobin  value  of 
the  erythrocytes.    Marestang's  studies1  of  the 
blood  of  several  sailors  during  a  sea  voyage  are  the  only  available 
proof  of  this  change. 

A  tropical  climate  of  itself  probably  does  not  affect  the  blood, 
although  it  offers  fruitful  factors  of  anemia  in  predisposing  to  such 
infections  as  the  malarial  fevers,  ankylostomiasis,  and  filariasis. 
So-called  tropical  anemia  is  more  often  apparent  than  actual. 


IV.  PATHOLOGICAL  CHANGES  IN  THE  ERYTHRO- 
CYTES. 

True  ameboid  movements  of  the  erythrocytes 
Ameboid      are  sometimes  observed,  as  the  result  of  the  effect 
Motility.     of  globulicidal  agents,  or  of  some  pathological 
state  of  the  blood,  such  as  a  severe,  high-grade 
anemia.    The  inherent  elastic  and  contractile  qualities  shown  by 
the  cells,  by  virtue  of  which  they  undergo  various  changes  in 
shape  while  floating  about  in  the  plasma,  must  not  be  confounded 
with  the  actual  ameboid  motility  which  they  exhibit  in  disease. 
The  oscillatory  dancing  movements  of  bits  of  fragmental  cor- 
puscles, and  the  characteristic  motility  of  the  intracellular  hyaline 
malarial  parasite,  also  must  be  distinguished  from  the  progres- 
sive, deliberate  characteristics  of  the  truly  ameboid  red  blood  cell. 

Within  the  body  the  hemoglobin  and  other 
Alterations    constituents  of  the  erythrocytes  are  preserved 
in  intact  within  the  corpuscular  stroma  by  the  com- 

Isotonicity.  position  of  the  blood  plasma,  which  is  such  that 
a  perfect  osmotic  balance  is  constantly  main- 
tained. Outside  of  the  body,  if  this  relationship  is  disturbed  by  the 
addition  of  distilled  water  to  a  specimen  of  blood,  thus  lowering 
the  concentration  of  the  plasma,  the  corpuscles  swell,  and  a  rapid 
discharge  of  hemoglobin  into  the  surrounding  tissue  ensues,  but  the 
addition  of  saline  solutions  of  a  definite  strength  prevent  such  a 
change.  Solutions  of  salts  of  just  sufficient  concentration  to  pre- 
serve the  corpuscles  and  to  prevent  removal  of  their  elements 
are  known  as  isotonic,  solutions  of  greater  strength  are  termed 
hypertonic,  and  those  of  lesser  strength,  hypotonic.  In  normal 
blood  it  has  been  determined  that  the  isotonicity  of  the  erythro- 
cyte usually  ranges  from  about  0.48  to  0.46  per  cent.  NaCl;  that 
is,  salt  solutions  of  this  concentration  are  just  sufficient  to  prevent 

1  Cited  by  von  Limbeck,  loc.  cit. 


PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES.  l8l 


the  discharge  of  hemoglobin  by  the  cell,  although  it  may  swell  by 
taking  up  water.  A  0.9  per  cent,  or  "normal"  salt  solution  not 
only  preserves  the  hemoglobin  within  the  cell,  but  also  prevents 
alterations  in  its  size  and  contour.  Hamburger1  and  others  have 
shown  that  alterations  in  isotonicity  depend  not  only  upon  changes 
in  the  plasma,  but  also  upon  the  constitution  of  the  erythrocytes 
themselves.  Fluctuations  in  the  amount  of  the  cells'  diffusible 
albumins,  chlorids,  and  phosphates  are  attended  by  corresponding 
osmotic  variations. 

Owing  to  the  conflicting  results  obtained  by  different  in- 
vestigators, the  isotonicity  of  the  erythrocytes  in  different  dis- 
eases is  of  little  clinical  value.  Stengel2  found  the  percentage 
0.52  and  0.6  in  two  cases  of  pernicious  anemia,  yet  in  other 
cases  the  figures  were  normal;  in  other  diseases  marked  by  ane- 
mia, such  as  carcinoma,  hepatic  cirrhosis,  renal  disease,  and 
tuberculosis,  he  found  that  the  variations  were  trivial.  Von  Lim- 
beck3 found  that  the  isotonicity  was  usually,  but  not  invariably, 
increased  in  high-grade  secondary  anemias,  in  leukemia,  and  in 
many  of  the  acute  injections,  while  it  was  decreased  in  chlorosis 
and  in  catarrhal  icterus.  A  decidedly  increased  isotonicity  was 
found  by  Vicarelli 4  in  pregnant  and  nursing  women.  As  a  gen- 
eral rule,  it  is  believed  that  degenerative  changes  in  the  erythro- 
cytes, whatever  their  nature,  predispose  to  dissociation  of  hemo- 
globin from  the  stroma,  and  that  in  such  instances  the  isotonic 
percentages  are  higher  than  normal. 

In  the  fresh  specimen  of  blood,  exaggeration 
Hypervis-      of  the  adhesive  properties  of  the  erythrocytes 
cosity.        may  be  observed  in  a  number  of  conditions,  but 
up  to  the  present  time  no  special  clinical  signifi- 
cance has  been  assigned  to  the  phenomenon.    It  occurs  to  some 
extent  in  most  inflammatory  diseases,  and,  according  to  Hayem,5 
is  often  seen  in  the  anemias  associated  with  marked  cachexia. 
'  Striking  examples  of  hyperviscosity  result  when  the  erythrocytes 
are  subjected  to  the  action  of  various  poisons,  notably  snake-venom, 
and  of  heterogeneous  pathological  blood  serum.    (See  p.  128.) 
From  the  effect  of  such  influences  the  erythrocytes,  instead  of 
forming  normal   rouleaux,  tend  to  adhere  in  large,  irregular 
masses  in  which  the  distinctive  characteristics  of  the  cells  are 
masked  or  lost.    The  individual  cells,  unattached  to  such  a  mass, 
may  exhibit  every  possible  variety  of  distortion,  losing  their  typi- 
cal biconcavity  and  regular  disc-like  appearance,  and  becoming 


^rch.  f.  Anat.  u.  Physiol.,  1886,  p.  476;  ibid.,  1887,  p.  31. 

2  Loc.  cit.  3  £oc>  cit. 

4  Cited  by  von  Limbeck,  loc.  cit.  s  j^oc 


1 82       ERYTHROCYTES,   BLOOD  PLAQUES,  AND  HEMOKONIA. 

converted  into  elongated,  misshapen  bodies.  It  frequently  happens 
that  the  cell  is  provided  with  one  or  more  long,  delicate  processes 
several  times  the  length  of  its  diameter,  this  being  due  to  the  ad- 
hesion of  a  bit  of  the  stroma  to  the  cover-glass  while  preparing  the 
specimen;  in  the  spread  film  it  will  be  noted  that  these  processes 
all  point  in  the  same  direction. 

Changes  in  the  shape  and  size  of  the  eryth- 
Deformities    rocytes  are  common  in  all  anemias  which  reach 
of  a  severe  grade,  the  degree  of  such  deformities 

Shape  and     corresponding  closely  to  the  intensity  of  the 
Size.         anemic  process.    The  diameter  of  the  cells  may 
be  more  or  less  uniformly  increased  or  decreased, 
and  such  pronounced  alterations  in  their  shape  may  occur  that 

many  of  them  bear  but 
slight  resemblance  to  the 
typical  discs  of  normal  blood 
(Plate  I ;  also  Fig.  46) .  Ab- 
normal inequality  in  the 
size  of  the  erythrocytes  is 
expressed  by  the  term  aniso- 
cytosis. 

When  the  corpuscle  be- 
comes greatly  enlarged  in 
diameter  it  is  known  as  a 
megalocyte  or  macrocyte,  the 
presence  of  large  numbers 
of  such  cells  being  known 
as  megalocytosis  or  macrocy- 
tosis.  The  diameter  of  a 
megalocyte  generally  varies 
from  9  to  12  [J.,  but  some- 
times much  larger  forms  are 
seen,  measuring  as  much  as  20  p..  They  are  present  in  the  severer 
anemias,  especially  in  the  pernicious  form,  in  which  they  constantly 
occur  in  large  numbers.  The  megalocyte  found  in  this  disease  is 
usually  characterized  by  an  excess  of  hemoglobin,  while  in  the 
secondary  anemias  such  cells  are  generally  deficient  in  their  hemo- 
globin content. 

The  smaller  forms,  the  microcytes,  illustrate  the  extreme  de- 
crease in  size  of  the  red  cell  under  pathological  conditions.  The 
microcyte  is  an  extremely  small  globular  body,  measuring  from 
about  3  to  5  fi  in  diameter.  It  is  found  in  all  the  varieties  of  ane- 
mia, but  is  most  commonly  associated  with  chlorosis  and  with 
the  moderately  developed  second  forms.  An  abundance  of 
microcytes  in  the  blood  is  known  as  microcytosis. 


Fig.  46. — Deformities  of  Shape  and  Size. 
Illustrating    various   grades  of  cell  deformity 
associated  with  severe   anemia.     The  large  nu- 
cleated erythrocyte  is  a  typical  megaloblast.  (Ehr- 
lich's  triacid  stain.) 


PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES.         1 83 

Eichhorst's  corpuscles  are  deeply  colored,  highly  refractive  mi- 
crocytes,  about  3  ft  in  diameter,  and  usually  of  regularly  spherical 
shape.  They  were  once  regarded  as  pathognomonic  of  pernicious 
anemia,  but  are  now  considered  diagnostic  of  no  especial  condi- 
tion, being  frequently  found  in  severe  anemias  of  any  type,  and 
often  being  absent  in  pernicious  anemia. 

It  seems  reasonable  to  infer  that  deformities  in  the  size  of  the 
erythrocyte  are  referable  chiefly  to  two  different  factors :  to  faulty 
hemogenesis  and  to  degenerative  changes  of  the  corpuscle  which 
lead  to  alterations  in  its  histological  structure.  Megalocytes,  for 
example,  may  in  some  instances  represent  an  actual  giantism  of 
the  cell,  bred  in  the  marrow  from  correspondingly  large-sized 
nucleated  antecedents ;  in  other  instances  (of  which  those  exceed- 
ingly pale,  "washed-out"  forms  are  examples)  their  abnormal 
size  may  be  attributed  to  hydropic  enlargement,  resulting  from 
their  imbibition  of  fluids  from  the  surrounding  plasma.  Micro- 
cytes  may  enter  the  circulating  blood  as  such,  or,  as  is  frequently 
the  case,  they  may  be  the  products  of  corpuscular  budding  and 
fragmentation. 

In  severe  forms  of  anemia,  characterized  by  excessive  cellular 
loss,  there  appears  also  to  be  a  tendency  toward  a  compensatory 
hypertrophy  of  many  of  the  erythrocytes,  in  order  thus  to  in- 
crease the  oxygen-carrying  capacity  of  the  blood,  which,  were  it 
not  for  these  numerous  megalocytes,  might  in  some  instances  be 
too  limited  to  sustain  life. 

'  Poikilocytes  are  erythrocytes  deformed  in  shape  as  the  result 
of  some  pathological  condition  of  the  blood.  Poikilocytosis,  the 
name  by  which  this  condition  is  designated,  is  akin  to  crenation 
in  so  far  as  in  both  conditions  the  cells  may  be  similarly  distorted 
and  misshapen.  But  it  is  unlike  crenation  for  the  reason  that 
poikilocytosis  is  a  pathological  condition,  and  demonstrable  the 
moment  the  blood  is  withdrawn  from  the  body;  while  crenation 
is  a  physiological  phenomenon  depending  upon  external  influences 
for  its  production,  and  never  occurring  until  the  blood  has  re- 
mained exposed  to  the  air  for  some  time.  Poikilocytes  may  be 
of  large  or  small  size,  the  varieties  of  deformities  being  infinite, 
and  the  degree  marked  or  slight  in  relation  to  the  nature  of  the 
blood  disease.  Some  of  the  cells  may  resemble  the  shape  of  a 
gourd  or  a  horseshoe ;  others  may  be  drawn  out  at  both  ends  until 
they  form  a  spindle-shaped  or  oval  body,  while  others  appear 
sharply  beaked  at  one  or  more  points,  or  shaped  like  a  dagger  or 
the  blade  of  a  tomahawk.  Occasionally  very  minute,  rapidly 
oscillating,  rod-shaped  forms  are  seen,  morphologically  not  unlike 
large,  unstained  bacilli — pseudo-bacilli  of  Hay  em.    These  rod- 


184      ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 


shaped  forms  are  products  of  corpuscular  fragmentation,  and 
indicate  lowered  vitality  and  feeble  powers  of  resistance  to  the 
pathological  influences  affecting  the  cells. 

Poikilocytosis  is  not  characteristic  of  any  single  disease  of  the 
blood,  but  it  is  generally  most  marked  in  the  grave  forms  of 
primary  anemia,  such  as  leukemia  and  pernicious  anemia.  Oval- 
shaped  red  cells  are  considered  by  Cabot 1  as  particularly  abundant 
in  the  latter  disease. 

The  conditions  of  deformity  affecting  the  shape  and  size  of  the 
erythrocytes  are  nearly  always  associated.  As  a  general  rule,  it 
may  be  stated  that  in  the  milder  types  of  anemia  small-sized, 
slightly  deformed  poikilocytes  and  microcytes  are  most  common; 
and  that  in  the  severe  forms,  large-sized,  conspicuously  distorted 

poikilocytes  and  megalocytes 
predominate. 

Loss  of 

Endoglobular  color  by  the 
Degeneration,  erythrocytes, 
which  pro- 
gresses hand  in  hand  with 
alterations  in  their  size  and 
shape  and  other  structural 
changes,  is  regarded  as  a  de- 
generative process  of  purely 
endoglobular  nature.  It  is 
observed  in  the  fresh  specimen 
of  blood  in  many  severe  ane- 
mic conditions,  especially  in 
the  anemias  associated  with 
infectious  diseases,  such  as  variola,  typhus  fever,  and  grave  septi- 
cemia and  pyemia  (Fig.  47). 

The  decoloration  may  commence  in  one  or  more  spots,  or  it 
may  equally  involve  the  whole  surface  of  the  corpuscle,  beginning 
at  its  center  and  spreading  progressively  toward  its  periphery. 
Clear,  hyaline  areas  of  oval,  round,  or  elongated  shape  appear 
within  the  stroma,  in  some  instances  sharply  contrasting  with  the 
relatively  dark  color  of  the  hemoglobin,  but  in  other  instances 
imperceptibly  blending  with  the  tint  of  the  surrounding  cell  body. 
The  active  motility  of  these  decolorized  spots  must  be  carefully 
distinguished  from  the  ameboid  movements  of  the  young  malarial 
parasite.  Complete  decoloration  transforms  the  cell  into  a  mere 
colorless  shell  or  "phantom,"  which  would  be  practically  invisible 

laA  Guide  to  the  Clinical  Examination  of  the  Blood,"  5th  ed.,  New 
York,  1904,  p.  131. 


Fig.  47. — Degenerative  Changes  in  the  Ery- 
throcytes.   (Fresh  Blood  Film.) 


PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES.         1 85 

were  it  not  for  its  faintly  colored  periphery.  Such  cells  are  known 
as  Ponfick's  shadow  corpuscles  or  as  Hayem's  achromacytes. 

Maragliano  and  Castellino 1  have  minutely  described  this  proc- 
ess of  decoloration,  along  with  certain  other  alterations  in  the 
structure  of  the  erythrocyte,  which  they  have  termed  endo globu- 
lar necrosis.  This  process  first  becomes  apparent  by  a  visible 
enlargement  of  the  central  concavity  of  the  corpuscle,  together 
with  a  simultaneous  fading  away  of  the  hemoglobin  in  this  situ- 
ation. This  central  area  of  pallor  gradually  spreads  toward  the 
periphery  of  the  cell,  until  finally  the  latter  alone  shows  evidence 
of  containing  coloring  matter.  Such  a  corpuscle,  when  examined 
on  cross-section,  appears  to  be  shaped  like  the  figure  8.  Frag- 
mentation of  this  delicate  rim  of  coloring  matter  may  occur,  in 
the  event  of  which  numerous  independent,  rod-like  bits  of  stroma 
are  formed.  The  decolorized  area  is  not  always  symmetrical,  so 
that  frequently  various  strikingly  bizarre  designs,  widely  differing 
in  shape  and  appearance,  may  be  observed,  It  has  been  deter- 
mined that  in  the  dried  blood  film  these  areas  of  decoloration  show 
a  decided  affinity  for  basic  stains,  such  as  methylene -blue  and 
thionin. 

Total  cellular  necrosis,  also  described  by  the 
Total        authors  mentioned  above,  represents  a  phase 

Necrosis.  of  structural  degeneration  in  the  erythrocyte 
of  more  advanced  development  than  the  endo- 
globular  changes.  This  process  begins  with  the  development  of 
several  small  elevations  or  corrugations  in  the  stroma  of  the  cor- 
puscle, which  gradually  multiply,  increase  in  size,  and  change  in 
shape  until  the  larger  portion  of  the  cell's  surface  is  thus  de- 
formed. Ameboid  movements  are  seen  to  begin,  as  if  the  entire 
cell  as  a  whole  were  involved,  the  final  stage  of  the  process  re- 
sulting in  the  formation  of  a  poikilocyte,  from  which  body  points 
and  small  fragments  are  observed  to  break  off  and  to  float  free 
in  the  plasma.  Decoloration,  starting  usually  from  a  single  point 
and  in  time  affecting  the  whole  stroma,  also  accompanies  this 
necrotic  alteration.  On  cross-section  the  cell  appears  as  an 
elongated,  thin  rod  with  rounded  poles.  This  fragmentation  of  the 
cells  is  spoken  of  as  schistocytosis.  The  erythrocytes  are  much 
more  resistant  than  the  leucocytes,  which  succumb  much  more 
readily  to  necrobiotic  influences. 

Endoglobular  degeneration  and  total  necrosis  of  the  erythro- 
cytes may  be  observed  both  in  normal  and  in  pathological  blood. 
In  normal  blood  they  occur  as  the  result  of  prolonged  contact 
with  the  air,  the  endoglobular  phase  becoming  first  apparent 

1  XI.  Cong.  f.  inn.  Med.,  Leipsic,  1892. 


1 86       ERYTHROCYTES,   BLOOD  PLAQUES,  AND  HEMOKONIA. 

within  from  thirty  to  seventy  minutes,  and  the  total  necrosis  in 
from  three  to  four  hours,  after  the  preparation  of  the  specimen. 
In  pathological  blood  the  changes  are  thought  to  be  due  chiefly 
to  increased  globulicidal  properties  of  the  plasma,  whereby  intra- 
vascular necrosis  is  excited,  and  partly  to  decreased  resistance 
of  the  erythrocytes,  in  consequence  of  which  their  degeneration  is 
abnormally  hastened  by  contact  with  normal  plasma  and  by 
exposure  to  extraneous  influences.  In  disease  it  follows  that 
they  are  demonstrable  immediately  or  very  shortly  after  the  blood 
•  has  been  withdrawn,  and  that  the  development  of  the  changes 
occurs  with  much  greater  rapidity  than  in  normal  blood.  The 
endoglobular  changes  are  regarded  as  a  more  favorable  prog- 
nostic sign  than  the  total  necrosis,  being  usually  associated  with 
anemias  of  less  severe  character  than  those  in  which  the  latter 
process  prevails. 

The   normal  erythrocyte,   when  fixed  and 
Atypical      stained  with  anilin  dyes,  according   to  one  of 
Staining  Re-  the  methods  described  in  another  section,  pos- 
action.      sesses  a  strong  affinity  for  a  single,  acid  stain; 

it  is  therefore  termed  monochromatophilic.  When 
solutions  are  used  containing  both  acid  and  basic  dyes,  such 
as  eosin  and  methylene-blue  or  eosin  and  hematoxylin,  the  nor- 
mal erythrocyte  is  always  stained  by  the  eosin;  and  with  Ehr- 
lich's  triple  mixture,  which  is  so  formulated  that  acid,  basic,  or 
so-called  neutral  principle  may  be  selected  by  the  elements  sub- 
jected to  its  action,  according  to  their  affinities,  the  erythrocyte 
invariably  is  colored  by  the  orange  G  of  the  mixture  (Plate  I). 

In  certain  morbid  conditions  some  of  the  corpuscles  lose  their 
affinity  for  the  acid  stain,  and  with  mixtures  of  both  acid  and 
basic  dyes  are  stained  atypically  by  either  or  both  elements. 
Such  corpuscles  are  said  to  be  polychromatophilic.  Thus,  when 
stained  with  an  eosin  and  methylene-blue  mixture,  they  are 
tinged  a  dirty  grayish-purple  or  violet,  instead  of  the  rose  color 
of  eosin;  and  with  the  triple  mixture  they  may  be  stained  pur- 
ple, reddish-brown,  or  pale  yellowish-pink,  flecked  here  and 
there  with  shadings  of  a  darker  red  (Plate  I). 

In  polychromatophilic  corpuscles  the  staining  is  likely  to  be 
very  unevenly  shaded,  often  being  quite  dark  in  spots,  especially 
around  the  periphery  of  the  cell  and  the  margin  of  the  nucleus, 
if  the  cell  be  nucleated.  These  color  changes  affect  not  only 
the  protoplasm,  but  the  nucleus  as  well,  and  are  strongly  em- 
phasized in  megaloblasts,  the  nuclei  of  which  may  show  every  sort 
of  color  combination.  The  more  deficient  the  corpuscle  in  hemo- 
globin, the  more  decided  its  polychromatophilic  tendency;  and 


PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES.  187 

the  more  strikingly  the  latter  is  developed,  the  more  intense  the 
cell's  affinity  toward  the  basic  element  of  the  stain. 

Polychromatophilia  may  occur  in  severe  forms  of  anemia  due 
to  any  cause,  and  it  is  especially  noted  in  two  of  the  primary 
varieties— pernicious  anemia  and  myelogenous  leukemia— in 
both  of  which  conditions  the  process  is  a  prominent  character- 
istic of  the  blood  picture.  Corpuscles  of  Poggi,  or  erythrocytes 
which  stain  with  basic  dyes  in  the  fresh,  unfixed  specimen,  are  also 
found  in  various  anemias.  They  probably  represent  immature 
elements  whose  presence  in  the  circulating  blood  reflects  stimulated 
hemogenesis. 

Nucleated  erythrocytes,  or  erythroblasts,  are 
Nucleation.  found  in  the  blood  of  the  adult  only  during  the 
existence  of  pathological  conditions,  but  occur 
in  large  numbers  in  the  blood  of  the  fetus,  and  occasionally  in 
the  infant  during  the  first  few  days  of  life.  Being  invisible  in  the 
fresh  blood,  they  must  be  studied  in  the  dried,  stained  specimen. 
In  such  preparations  the  finer  structure  of  their  nucleus,  which 
bears  a  special  affinity  for  the  basic  anilin  dyes,  may  be  beauti- 
fully illustrated  by  the  use  of  solutions  containing  methylene- 
blue,  methyl-green,  and  hematoxylin. 

According  to  their  size  and  nuclear  characteristics  the  ery- 
throblasts are  designated  as  normoblasts,  megaloblasts,  and  mi- 
croblasts.  Certain  intermediate  forms  are  also  common,  some- 
times termed  mesoblasts,  such  cells  being  atypical,  and  sharing 
characteristics  of  both  the  normoblast  and  the  megaloblast. 

Normoblasts  (Plate  I).— The  normoblast  is  a  nucleated  ery- 
throcyte of  about  the  general  size  and  shape  of  the  normal  erythro- 
cyte. In  the  typical  mature  cell  the  nucleus  is  round  or  ovoid  in 
shape,  very  deeply  stained,  and  situated  rather  toward  the  periph- 
ery of  the  cell  than  in  the  exact  center,  its  diameter  approximating 
more  than  one-half  that  of  the  corpuscle  which  it  occupies.  In  the 
normoblast  of  an  earlier  developmental  stage  the  nucleus  is  rela- 
tively larger  and  is  composed  of  delicate,  faintly  basic  chromatin 
—hall-marks  of  histological  youth.  In  some  of  the  typical  cells 
the  nucleus  appears  to  have  become  partly  or  completely  extruded 
from  the  protoplasm,  lying  either  somewhat  over  the  periphery  of 
the  cell  or,  being  completely  detached  from  it,  free  in  the  plasma 
(Fig.  49,  III).  The  nucleus  may  be  single,  or  partly  divided  by 
constricting  bands  of  chromatin  into  a  figure  like  a  dumb-bell  or 
a  clover-leaf,  or  completely  divided  into  several  small,  round 
sections.  More  rarely,  karyokinesis  may  be  observed,  the  diaster 
and  early  convolution  stages,  with  an  intact  but  plainly  con- 
stricted cell  body,  being  the  phases  ordinarily  found.    (Plate  I, 


1 88       ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 


Fig.  3;  also  Fig.  49,  II.)  In  carefully  stained  films  it  will  be 
noted  that  the  nuclear  framework  of  the  typical  normoblast 
consists  of  a  rather  sharply  defined  network  of  chromatin  hav- 
ing relatively  wide  intervening  open  spaces,  so  that  the  general 
appearance  of  the  nucleus  is  not  unlike  that  of  a  coarse  net. 

The  protoplasm  of  this  cell  is  usually  of  regular  outline  along 
the  periphery,  stains  somewhat  more  intensely  than  that  of  the 
normal  erythrocyte,  and  may  show  distinct  evidences  of  poly- 
chromatophilia,  this  characteristic  being  especially  marked  in  forms 
with  dividing  nuclei. 

The  normoblast  is  regarded  as  the  immediate  antecedent  of  the 
normal  erythrocyte  or  normocyte,  into  which  it  becomes  trans- 
formed by  the  loss  of  its  nuclear  structure.    The  exact  manner 
m  which  the  nucleus  is  disposed  of  has  long  been  a  bone  of  con- 
tention among  histologists,  and  even  at  the  present  time  views  on 
this  question  should  be  held  but  tentatively,  notwithstanding  many 
exhaustive  investigations,  especially  those  of  the  German  school. 
According  to  the  views  of  Rindfleisch,1  it  is  lost  by  extrusion 
from  the  cell  body,  which  thus  becomes  a  normal  erythrocvte, 
while  the  free  nucleus,  to  which  a  small  fringe  of  protoplasm  still 
remains  adherent,  collects  from  the  plasma  material  by  virtue  of 
which  it  ultimately  develops  into  a  new  erythroblast.  Ehrlich2 
believes  that  in  blood  rich  in  normoblasts  a  series  of  connected 
pictures  may  be  observed,  showing  that  the  normoblast  becomes 
transformed  into  the  erythrocyte  by  the  extrusion  or  emigration 
of  the  nucleus.    The  later  investigations  of  Neumann  and  Kol- 
hker,3  however,  tend  to  prove  that  the  nucleus  is  disposed  of  by 
its  destruction  and  absorption  within  the  cell,  and  that  its  ap- 
parent extrusion  from  the  stroma  is  simply  the  result  of  mechan- 
ical influences.    Pappenheim  and  Israel4  also  believe  that  the 
normoblast's  nucleus  disappears  by  decay  and  solution  within  the 
body  of  the  corpuscle,  and  that  the  apparently  extruded  nuclei 
are  to  be  taken  as  an  evidence  of  plasmolysis,  or  a  solution  of 
the  protoplasm  of  the  cells  once  containing  nuclei.    To  attempt 
a  reconciliation  of  these  diametrically  opposed  views  is  a  task  for 
future  workers  to  undertake.    Meanwhile,  the  general  trend  of 
opinion  inclines  toward  the  theory  of  nuclear  solution  within 
the  corpuscle,  and  regards  the  so-called  free  nuclei  of  the  normo- 
blasts simply  as  artefacts  (Fig.  49,  I  and  III). 

Normoblasts  exist  in  the  red  bone  marrow  of  the  normal  indi- 

1  Arch.  f.  mik.  Anat.,  1880,  vol.  xvii,  p.  1. 

2  Loc.cit.  3  Zeitschr.  f.  klin.  Med.,  1881,  vol.  iii,  p.  411. 
Virchows  Arch.,  1896,  vol.  cxlv,  p.  587;  also  Pappenheim,  InauR.  Dis- 
sert., Berlin,  1895.  0 


PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES.  l8o 

victual,  but  are  found  in  the  circulating  blood  only  when  the 
marrow,  in  consequence  of  pressing  demands  made  upon  it  for 
the  rapid  manufacture  of  new  erythrocytes,  becomes  unable  to 
furnish  an  adequate  supply  of  perfectly  developed  cells,  so  that 
some  of  these  immature,  nucleated  forms  prematurely  leave  their 
birthplace  in  the  marrow,  and  pass  into  the  blood  stream  in  com- 
pany with  large  numbers  of  mature,  non-nucleated  discs.  Normo- 
blasts are  associated  with  lesions  in  which  active  hemogenesis 
of  the  normal  type  is  stimulated,  being  the  prevailing  type  of 
erythroblast  in  the  anemias  resulting  from  hemorrhage  and  in 
other  severe  anemias  of  a  secondary  type.  They  sometimes  ap- 
pear in  the  blood  in  successive  crops  of  large  numbers  during  the 
course  of  certain  severe  anemias,  this  phenomenon  having  been 
termed  by  von  Noorden 1  a  blood  crisis.  Blood  crises,  which  are 
of  abrupt  onset  and  of  brief  duration,  lasting  but  a  few  hours, 
are  usually  the  direct  precursors  of  an  increase  in  the  erythro- 
cyte count  and  in  the  hemoglobin  percentage,  being  therefore 
a  favorable  sign,  indicating  regeneration  of  the  blood.  They  occur 
with  especial  frequency  after  loss  of  blood  from  hemorrhage  and 
in  chlorosis,  and  are  not  uncommon  in  long-standing  cases  of 
myelogenous  leukemia  and  primary  pernicious  anemia,  in  which 
diseases  periods  of  temporary  improvement  are  likely  to  take  place 
from  time  to  time. 

Megaloblasts  (Plate  I;  also  Fig.  48).— The  typical  megaloblast 
is  much  larger  in  size  than  the  normoblast,  and  contains  a  single, 
large,  pale-staining  nucleus  which  occupies  the  greater  part  of  the 
cell  body.  Both  cell  and  nucleus  are  round  or  ovoid  in  shape,  the 
diameter  of  the  former  being  from  about  n  to  20  n,  and  that  of  the 
latter  from  6  to  10  fi.  The  greatest  extremes  of  these  measurements 
apply  to  those  forms  which  are  seen  with  relative  infrequency,  for 
the  megaloblast  most  commonly  observed  does  not  usually  measure 
more  than  12  ft  in  diameter,  with  a  nucleus  of  proportionate  size. 
The  nucleus,  which  may  be  situated  either  in  or  away  from  the 
center  of  the  cell,  is  composed  of  a  chromatin  network  having 
relatively  small  intervening  open  spaces,  so  that  the  nuclear 
structure  is  decidedly  more  delicate  and  less  well-defined  than  that 
of  the  normoblast.  With  the  triacid  solution  and  with  the  Roman- 
owsky  stain  it  is  tinted  pale  green  or  blue,  or  it  may  show  every  sort 
of  irregular  tinctorial  reaction  to  the  anilin  dyes,  certain  portions 
being  deeply  stained,  while  other  parts  are  but  faintly  colored;  the 
undertone  of  green  or  blue  is  frequently  stippled  with  fine  dots  of 
purple  or  of  brilliant  crimson,  especially  about  the  periphery;  or 
it  may  be  mottled  and  splotched  here  and  there  with  areas  of  purple 

1  Charite-Annalen,  1891,  vol.  xvi,  p.  217. 


190      ERYTHROCYTES,  BLOOD  PLAQUES,   AND  HEMOKONIA. 

or  of  dark  blue.  The  nucleus,  in  the  triple-stained  film,  usually 
is  sharply  differentiated  from  the  body  of  the  cell  by  a  distinct 
white  margin  which  encircles  it  and  is  thrown  out  in  bold  relief  by 
the  deep  staining  of  the  nuclear  and  cell  bodies  on  either  side. 
Occasionally  a  megaloblast  shows  a  coarse,  small  nucleus  of  very 
basic  affinity,  resembling  that  of  the  normoblast- — characteristics  of 
nuclear  senility. 

The  protoplasm  of  the  megaloblast  often  seems  swollen  and 
enlarged,  and  appears  to  contain  areas  of  depression  and  elevation 
at  different  points;  it  is  sometimes  quite  round  or  oval  in  contour, 
and  sometimes  more  or  less  deformed.  It  is  usually  polychro- 
matophilic,  and,  like  the  nucleus,  may  show  the  greatest  variety 

of  color  combinations.  Some 
cells  stain,  with  the  triacid  mix- 
ture, a  dull  brownish-yellow 
color  with  deeper  shadings  of 
a  burnt-sienna  tint  in  the 
neighborhood  of  the  nucleus 
and  of  the  periphery;  others 
have  an  undertone  of  crimson, 
as  if  the  stain  contained  an 
excess  of  fuchsin,  and  are 
streaked  and  dotted  with  yel- 
low and  tan-colored  patches; 
still  others  stain  a  diffuse  pur- 
ple, blending  in  spots  into  a 
light  pink.  With  Wright's 
stain  the  color  varies  from 
greenish-blue  to  purple  to  dull 
yellow.  Mitotic  megaloblasts, 
with  figures  similar  to  those 
exhibited  by  normoblasts  thus 
dividing,  are  met  with  occasionally  in  anemias  of  great  severity. 
(Plate  I,  Fig.  3;  also  Fig.  49,  II.) 

The  megaloblast  is  an  element  of  the  bone  marrow  of  the  young 
fetus,  and  is  totally  foreign  both  to  the  marrow  and  to  the  blood  of 
the  normal  adult.  According  to  the  views  of  Ehrlich,  it  repre- 
sents the  immediate  antecedent  of  the  megalocyte,  into  which  it 
develops  by  the  absorption  of  its  nucleus.  Apparent  extrusion 
of  megaloblastic  nuclei  is  never  observed.  Megaloblasts  are 
found  in  the  circulating  blood  only  under  conditions  in  which  the 
blood-making  organs  have  reverted  more  or  less  to  the  fetal  type, 
so  that  their  presence  in  the  circulation  is  considered  to  indicate  that 
a  sluggish  hemogenesis  of  embryonal  character  exists.  The 


Fig.  48. — Megaloblasts. 
Common  types  of  megaloblasts,  showing  va- 
riations in  size  and  shape  and  peculiarities  of  the 
nuclear  structure.    (Ehrlich's  triacid  stain.) 


PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES.  IQI 

significance  of  megaloblasts,  therefore,  is  diametrically  opposed 
to  that  of  normoblasts,  for,  while  the  latter  are  regarded  as  an 
expression  of  blood  regeneration  and  are  considered  to  be  of 
favorable  prognostic  significance,  the  former  must  be  looked  on 
as  an  evidence  of  degeneration  of  the  hematopoietic  organs,  and, 
consequently,  are  of  grave  prognosis. 

In  the  following  table  the  principal  points  of  distinction  between 
the  typical  normoblast  and  the  megaloblast  are  emphasized: 


Normoblast. 

Megaloblast. 

Size. 

7.5  to  10  (l. 

11  to  20  /J. 

Nucleus. 

Sharply  defined. 
Intensely  basic. 
Coarsely  meshed. 
Occupies  about  one-half  of 
cell  body. 

Dully  defined. 

Feebly  basic. 

Delicately  meshed. 

Occupies  greater  part  of  cell  body. 

Protoplasm. 

Sometimes     very  scanty 
and  of  ragged  outline. 
Occasionally  polychro- 
matophilic. 

Frequently  appears  swollen;  out- 
line fairly  regular,  but  surface 
undulating  in  many  cells. 

Striking  tendency  toward  poly- 
chromatophilia. 

Histological 
Significance. 

Typical  of  active,  adult 
hemogenesis. 

Typical   of   sluggish,  embryonal 
hemogenesis. 

Occurrence. 

Prevailing   type   of  ery- 
throblast     in  anemias 
with    active    blood  re- 
generation. 

Prevailing  type  of  erythroblast  in 
anemias  with  megaloblastic  de- 
generation of  the  bone  marrow. 

Megaloblasts  are  found  in  the  blood,  almost  invariably  in  as- 
sociation with  normoblasts,  in  various  anemias  of  marked  severity, 
but  in  only  three  conditions,  viz.,  primary  pernicious  anemia, 
certain  cases  of  anemia  due  to  Bothriocephalus  latus  infection, 
and  nitrobenzol  poisoning,  have  these  cells  been  found  to  con- 
stitute the  prevailing  type  of  erythroblast. 

In  pernicious  anemia  the  prevalence  of  megaloblasts  is  gener- 
ally admitted  to  be  a  sign  that  in  this  disease  the  bone  marrow, 
in  consequence  of  its  reversion  to  a  fetal  type,  throws  into  the 
blood  stream  large  numbers  of  these  blood  cells  of  embryonal 
character,  these  degenerative  changes,  the  presence  of  megalo- 
blasts, overshadowing  the  regenerative  changes,  or  the  presence 
of  normoblasts.  In  bothriocephalus  anemia,  in  which  also  the 
megaloblasts  may  outnumber  the  normoblasts,  it  is  believed  that 
the  toxins  produced  by  the  parasite  cause  changes  in  the  hema- 
topoietic organs  precisely  similar  to  those  found  in  pernicious 
anemia.    Rosenquist's 1  elaborate  studies  show  that  the  excessive 

1  Berlin,  klin.  Wochenschr.,  iqoi,  vol.  xxxviii,  p.  666. 


IQ2       ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 

albumin  disintegration  caused  by  the  bothriocephalus  toxin  is 
essentially  like  that  occurring  in  typical  pernicious  anemia.  In 
a  single  case  of  nitrobenzol  poisoning,  reported  by  Ehrlich  and 
Lindenthal,1  large  numbers  of  erythroblasts  were  noted;  normo- 
blasts predominated  at  first,  but  in  the  later  stages  of  the  intoxica- 
tion they  were  outnumbered  by  megaloblasts.  In  other  grave 
anemias,  notably  in  leukemia,  the  regenerative  signs  appear  to 
be  more  active  than  the  degenerative,  for,  while  in  these  condi- 
tions megaloblasts  are  frequently  found,  they  are  never  so  numer- 
ous as  the  normoblasts. 

Microblasts. — The  microblast,  which  is  the  rarest  form  of  nu- 
cleated erythrocyte,  is  a  cell  usually  not  larger  than  5  or  6  p-  in 
diameter,  and  often  of  smaller  size.  It  consists  of  a  deeply  stained, 
round  nucleus  like  that  of  the  normoblast,  encircled  by  a  frag- 
ment of  ragged  protoplasm  of  a  dull  brownish-yellow  tint,  in  films 
stained  with  the  triacid  solution.  Wright's  stain  frequently 
colors  this  stroma  blue.  Microblasts  are  thought  to  be  simply 
forms  of  the  normoblast  in  a  more  or  less  advanced  stage  of 
protoplasm  degeneration,  this  process  accounting  for  the  char- 
acteristic scantiness  and  frayed-out  appearance  of  their  cell  body. 
Their  clinical  significance,  naturally,  is  identical  with  that  of  the 
normoblast. 

From  what  has  been  stated,  it  may  be  concluded  that  nor- 
moblasts and  megaloblasts  constitute  two  distinct  classes  of 
nucleated  erythrocytes,  each  evidencing  a  separate  type  of  blood- 
formation,  and  each  carrying  a  different  clinical  meaning.  Nor- 
moblasts, being  an  adult  type  of  cell,  have  sharply  defined,  dense, 
deeply  stained  nuclei;  megaloblasts,  being  an  embryonal  type  of 
cell,  have  poorly  defined,  delicate,  feebly  stained  nuclei. 

Atypical  Erythroblasts. — In  some  of  the  severer  anemias, 
notably  in  myelogenous  leukemia  and  in  pernicious  anemia, 
various  atypical  erythroblasts  are  frequently  found,  corresponding 
partly  to  one  and  partly  to  the  other  of  the  first  two  species  of  cells 
described  above.  These  so-called  "mesoblasts,"  which  may  be  re- 
garded either  as  normoblasts  with  immature  nuclei  or  as  megalo- 
blasts with  mature  nuclei,  are  in  some  instances  almost  as  numerous 
as  the  typical  forms  of  erythroblasts.  It  is  sometimes  impossible 
accurately  to  determine  to  which  type  such  cells  belong,  but 
usually  they  may  be  classified  by  taking  size  as  a  criterion  for 
differentiation.  Those  approximating  the  normocyte  in  size  may 
safely  be  classed  as  normoblasts;  those  of  larger  size,  as  megalo- 
blasts— regardless  of  their  nuclear  peculiarities.    The  two  fol- 

1  Zeitschr.  f.  klin.  Med.,  1896,  vol.  xxx,  p.  427. 


PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES.         1 93 

lowing  commoner  forms  of  atypical  erythroblasts  may  be  rec- 
ognized : 

1.  Corpuscles  about  8  or  10  ft  in  diameter,  containing  a  rela- 
tively large,  round  or  ovoid  nucleus,  composed  of  a  finely  meshed 
chromatin  framework.    The  nucleus  is  pale,  and  is  often  filled  with 


m 


Fig.  49. — -Atypical  Forms  of  Erythroblasts. 
.■u  1'  Myoblasts  and  normoblasts  showing  nuclear  solution;  the  two  cells  (a)  show  early,  and 
the  three  {b)  late  stages  of  karyolysis.  Five  of  the  six  cells  (c)  contain  nuclear  remains  consisting 
ot  both  coarse  and  delicate  chromatin  masses.  Note  the  granular  basophilia  in  the  groups  of  cells 
at  1,  11,111,  and  IV.  //.Erythroblasts  with  multiple  and  dividing  nuclei;  the  megaloblast  (a) 
represents  the  wreath-shaped  (monaster)  stage  of  karyokinesis,  the  megaloblast  (b)  the  double  star- 
shaped  (chaster)  stage  and  the  megaloblast  (c)  the  convolution  (daughter  cell)  stage.  The  other 
cells  illustrate  the  kinds  of  erythroblasts  with  convoluted  and  multiple  nuclei  ordinarily  found 
in  high-grade  anemias.  ///,  Erythroblasts  showing  so-called  nuclear  extrusion.  IV,  Erythro- 
cytes containing  ring  bodies.    V,  Normal  erythrocytes.    (Wright's  stain.) 


finely  stippled  areas  of  acid  affinity.  The  cell  body  is  usually  of 
regular  outline,  and,  as  a  rule,  is  decidedly  polychromatophilic. 
Such  cells  may  be  regarded  as  immature  forms  of  normoblasts, 
with  which  they  may  properly  be  classed  in  the  differential  count 
(Plate  I;  also  Fig.  48). 
13 


1 94      ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 

2  Corpuscles  about  12  to  15  in  diameter,  having  a  small, 
coarsely  meshed  nucleus  not  exceeding  2  or  3  fx  in  diameter,  and, 
as  a  rule,  situated  eccentrically.  The  nucleus  stains  very  basically, 
and  may  or  may  not  be  separated  from  the  protoplasm  by  a  color- 
less zone  The  body  of  the  cell  is  round  or  ovoid,  and  stains 
faintly  This  form  of  cell  appears  to  carry  the  same  clinical 
significance  as  the  megaloblast,  of  which  it  is  probably  a  late 
developmental  phase  (Plate  I;  also  Fig.  48).  . 

RinR  Bodies.— In  severe  anemia  Wright's  stain  often  brings  out 
peculiar  intra-  and  extra- cellular  ring-shaped  bodies  whose  outlines 
resemble  those  of  the  nuclear  figures  of  erythroblasts  (Fig.  49, 
IV)     Cabot,1  who  described  these  bodies,  suggests  that  they  may 
represent  nuclear  remnants,  or  portions  of  the  erythrocytes  nuclei 
which  are  especially  resistant  to  whatever  forces  ultimately  destroy 
the  cells  and  their  nuclei.    Basic  (blue)  ring  bodies  within  the 
erythrocytes  were  described  and  pictured,  m  1901,  by  btrauss 
and  Rohnstein,2  who  interpreted  them  as  a  variety  of  granular 
basophilia.    The  bodies  have  been  found,  in  association  _  with 
frankly  nucleated  erythrocytes,  polychromatophiles,  and  basically 
stippled  cells,  in  lead  poisoning,  in  pernicious  anemia,  and  m 
lymphatic  leukemia.    The  writer  has  noted  them  m  high-grade 
anemia  secondary  to  sepsis.    With  Wright's  solution  the  ring- 
shaped  bodies  stain  red  and,  rarely,  blue;  they  are  variously 
shaped-circles,  rude  rosettes,  clover  leaves,  figures-of-eight  and 
forms  with  twisted  threads  and  with  netted  structures.  These 
designs,  it  will  be  noted,  correspond  accurately  to  the  nuclear 
figures  of  various  erythroblasts.  m         m  m 

In  certain  of  the  severe  anemias,  staining  with 
Granular    methylene-blue  shows  a  peculiar  granular  condi- 
Basophilia.    tion  of  the  protoplasm  in  some  of  the  erythro- 
cytes, attention  first  having  been  called  to  this 
fact  by  von  Noorden,3  who  demonstrated  the  basophilic  charac- 
ters of  such  granules,  and  described  their  occurrence  m  vari- 
ous pathological  states.    Many  of  the  corpuscles  thus  affected 
are  of  the  nucleated  form,  but  non-nucleated  cells  may  be  simi- 
larly granulated;  as  a  rule,  such  corpuscles  are  also  strikingly 
polychromatophilic. 

The  granules  appear  either  as  fine  or  as  coarse,  stippled  areas 
staining  intensely  with  the  basic  stain,  and  distributed  through 
the  body  of  the  cell  either  quite  uniformly  or  m  localized  patches 

1  Jour.  Med.  Research,  1903,  vol.  iv,  p.  15-  „  Eerlin 

2 -Die  Blutzusammensetzung  bei  den  verschiedenen  Anamienen,  Berlin, 


1901,  p.  224. 

3  Charite-Annalen,  1892,  vol.  xvu,  p.  202. 


PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES.  195 


at  one  or  at  several  points.  In  some  cells  they  are  exceedingly 
fine  and  closely  packed  together,  so  that  at  first  glance  the  whole 
protoplasm  appears  to  be  a  homogeneous  mass  of  purplish  dis- 
coloration; in  others  the  protoplasm  is  dotted  here  and  there 
with  coarse  granules,  not  more  than  five  or  six  being  found 
in  the  whole  cell;  still  others  may  contain  both  fine  and  coarse 
granules  irregularly  sprinkled  over  the  surface  (Plate  I;  also 
Figs.  49  and  50). 

The  occurrence  of  somewhat  similar  granulations  in  the  eryth- 
rocytes of  the  embryo  has  been  noted  by  Engel,1  Pappenheim,2 
and  others,  who  regard  them  as  nuclear  debris,,  the  product  of 
nuclear  disintegration.    Such  an  origin  in  embryonic  blood  is 


Fig.  50. — Granular  Basophilia. 
Erythrocytes  showing  various  degrees  of  basophilia,  with  fine,  coarse,  spherical,  ovoid,  and  spicu- 
lateigranules.    Note  the  basophilic  normoblast.    (Wright's  stain.) 


probably  physiological.  In  post-uterine  life,  however,  this  proc- 
ess is  to  be  regarded  as  a  sign  of  stroma  degeneration,  arising 
in  all  likelihood  through  the  influence  of  various  blood  poisons. 
In  some  instances  the  change  precedes  all  other  recognizable  alter- 
ations in  the  blood,  and  appears  as  the  first,  and,  indeed,  some- 
times the  only,  distinct  sign  of  anemia. 

Granular  basophilia  of  the  erythrocytes  has  been  noted  with 
more  or  less  constancy  in  these  conditions:  pernicious  anemia, 
leukemia,  Hodgkin's  disease,  so-called  tropical  anemia,  bothrio- 
cephalus  anemia,  malarial  fever,  sepsis,  carcinoma,  long-standing 
suppurative  lesions,  and  chronic  lead  poisoning.    In  chlorosis,  if 


1  Verhandl.  d.  Vereins  f.  inn.  Med.  z.  Berlin,  1898-99,  vol.  xviii,  p.  216. 

2  Loc.  cit. 


I96      ERYTHROCYTES,  BLOOD  PLAQUES,  AND  HEMOKONIA. 

uncomplicated  by  symptoms  of  intestinal  auto-intoxication,  the 
erythrocytes  do  not  exhibit  this  alteration;  granule  cells  are  also 
absent  in  syphilis,  in  acute  injections  diseases,  in  chronic  lesions 
oj  the  kidney  and  the  liver,  and  in  diabetes,  according  to  Grawitz.1 
Regarding  the  occurrence  of  this  change  in  pernicious  anemia, 
Ehrlich 2  believes  that  the  number  of  granule  cells  in  the  blood 
bears  a  certain  relation  to  the  severity  of  the  disease,  stating  that 
they  decrease  and  often  disappear  during  the  periods  of  remission, 
reappearing  as  the  other  blood  changes  again  become  evident. 
On  the  other  hand,  Litten,3  who  asserts  that  he  has  found  these 
basophilic  granulations  in  one-tenth  of  all  cases  of  anemia,  has 
been  unable  to  determine  their  clinical  significance  from  either 
a  diagnostic  or  a  prognostic  point  of  view.  The  studies  of 
Grawitz  and  Hamel4  show  that  granular  degeneration  of  the 
erythrocytes  occurs  with  great  regularity  in  saturnism,  both 
in  obscure  and  in  well-marked  cases,  and  these  authors  attach 
considerable  diagnostic  value  to  this  fact,  concluding  that  the  sign 
is  important  in  the  diagnosis  of  lead  poisoning  in  patients  in  whom 
the  intoxication  is  merely  suspected,  being  evidenced  by  no  other 
definite  symptoms.  Experimentally,  basophilia  has  been  produced 
by  the  administration  of  lead  salts,  tin  chlorid,  copper,  pyrodin, 
atropin,  toluylendiamin,  and  phenylhydrazin.  A  dose  of  any  of 
the  proprietary  preparations  of  hemoglobin  may  also  promptly 
excite  the  change,  as  may  the  ingestion  of  whole  blood- 
facts  which  lead  Grawitz5  to  assume  that  blood  in  the  gastro- 
intestinal canal  elaborates  toxic  substances  the  absorption  of  which 
acts  deleteriously  upon  the  erythrocytes.  This  and  other  phases 
of  basophilia  have  been  reviewed  at  length  by  the  writer  elsewhere.6 

Here  may  be  mentioned  certain  areas  of  reddish  stippling 
(S chuff ner's  granules)  demonstrated  by  polychrome  methylene- 
blue  in  the  erythrocytes  of  tertian  malarial  fever  (q.  v.). 

Oligocythemia,  or  diminution  in  the  number  of 

Oligocy-      erythrocytes  below  the  normal  standard,  is  pres- 

themia.      ent  to  a  more  or  less  marked  degree  in  all  forms 
of  anemia,  being  associated,  naturally,  with  an 
oligochromemia,  or  diminution  in  the  percentage  of  hemoglobin, 
but  not  necessarily  with  an  oligemia,  or  reduction  in  the  volume 
of  the  blood  mass. 

The  loss  of  corpuscles  may  be  slight  or  it  may  be  marked,  ac- 
cording to  the  nature  of  the  anemia  of  which  it  is  symptomatic. 

1  Amer.  Jour.  Med.  Sci.,  1900,  vol.  cxx,  p.  277. 

2  hoc.  cit.  3  Deutsch.  med.  Wochenschr.,  1899,  vol.  xxv,  p.  717. 

4  Deutsch.  Arch.  f.  klin.  Med.,  1900,  vol.  lxvii,  p.  357. 

5  Deutsch.  med.  Wochenschr.,  1901,  vol.  xxvii,  p.  908. 

6  Amer.  Med.,  1903,  vol.  v,  p.  571. 


PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES. 


The  most  striking  examples  of  oligocythemia  are  encountered 
after  hemorrhages  involving  the  loss  of  a  large  amount  of  blood 
and  in  pernicious  anemia;  while  in  chlorosis  and  in  the  majority 
of  the  secondary  anemias  the  decrease  is  relatively  less  marked. 
The  following  summary  of  the  averages  of  fifty  consecutive  counts 
each  in  cases  of  primary  and  secondary  anemia  illustrates  the 
various  degrees  of  cellular  loss  which  ordinarily  accompany  these 
conditions  : 

Erythrocytes  per  c.mm. 

 1,152,470 

 2>720>763 

 3,642,900 

 4,111,000 


Average  of  50  Counts. 
In  pernicious  anemia. . . 

"  leukemia   

"  secondary  anemia... 
"  chlorosis   


It  is  impossible  to  designate  the  degree  of  oligocythemia  which 
may  exist  without  a  fatal  outcome,  although  a  number  of  author- 
ities have  attempted  to  set  fixed  limits  beyond  which  reduction 
m  the  number  of  erythrocytes  is  supposed  to  cause  death.  The 
effects  of  a  blood  loss  are  so  diverse  in  different  individuals  that 
all  such  arbitrary  rules  must,  of  necessity,  prove  practically 
valueless.  It  should  be  remembered  that  while  in  some  persons 
a  comparatively  moderate  decrease  may  prove  fatal,  in  others  a 
most  astonishing  loss  is  compatible  with  life.  It  may  be  stated 
m  general  terms  that  few  individuals  recover  in  whom  a  count  of 
less  than  500,000  erythrocytes  to  the  c.mm.  is  found,  although 
occasional  exceptions  to  this  rule  have  been  reported. 

Whether  or  not  an  actual,  permanent  polycy- 
Pol yc ythemi A .  themia,  or  an  increase  in  the  number  of  erythro- 
cytes above  the  normal  standard,  exists  is  still 
an  unsettled  question,  but  the  majority  of  authorities  maintain 
that  such  a  condition  is  due  merely  to  some  physical  change 
producing  concentration  of  the  blood,  or  unequal  distribution  of 
the  corpuscles,  in  favor  of  the  peripheral  blood  vessels.  In  health, 
it  would  not  seem  unreasonable  to  suppose  that  a  moderate  de- 
gree of  polycythemia  may  be  habitual  in  the  strong,  overdevel- 
oped adult,  whose  blood-making  organs  are  possibly  developed 
proportionately  to  the  other  parts  of  his  system.  In  pathological 
conditions  there  is  nothing  tangible  upon  which  to  base  the  belief 
that  an  actual  and  permanent  overproduction  of  the  erythro- 
cytes ever  takes  place,  the  polycythemia  associated  with  certain 
diseases  being  satisfactorily  accounted  for  by  coexisting  physical 
conditions,  m  no  way  peculiar  to  the  lesion  in  question.  While 
it  is  true  that  in  some  conditions  it  is  not  always  possible  to  ex- 
plain the  increase  by  purely  physical  causes,  still  there  is  no  posi- 


198      ERYTHROCYTES,   BLOOD  PLAQUES,  AND  HEMOKONIA. 


tive  proof,  in  these  instances,  that  the  change  is  pathological. 
There  seems,  therefore,  no  evidence  to  warrant  an  arbitrary  clas- 
sification of  polycythemia  into  two  divisions,  actual  and  relative, 
as  some  authors  have  suggested. 

The  cause  of  polycythemia,  then,  may  be  attributed  to  physio- 
logical factors  such  as  concentration  of  the  blood,  increased  blood 
pressure,  peripheral  stasis,  increased  viscidity  of  the  erythrocytes, 
and  their  unequal  distribution  through  the  circulatory  system. 

The  polycythemia  associated  with  various  physiological  and 
pathological  conditions  will  be  considered  under  their  appropriate 
headings.  Briefly,  an  increase  of  erythrocytes  over  the  normal 
number  is  found  in  the  following  conditions : 

1.  In  the  new-born. 

2.  After  taking  food. 

3.  In  starvation. 

4.  During  residence  in  high  altitudes. 

5.  From  the  effect  of  cold  and  hot  baths,  muscular  exercise, 
massage,  and  electricity. 

6.  From  the  administration  of  lymphagogues,  emetics,  pur- 
gatives, and  thyroid  extract. 

7.  During  active  blood  regeneration. 

8.  During  reformation  of  an  exudate  after  aspiration. 

9.  After  urinary  crises,  diaphoresis,  emesis. 

10.  In  poisoning  by  illuminating  gas  and  by  phosphorus. 

11.  In  Asiatic  cholera,  dysentery,  and  diarrhea. 

12.  In  acute  yellow  atrophy  of  the  liver  and  myxedema. 

13.  In  conditions  of  cyanosis  and  peripheral  stasis,  for  example, 
uncompensated  organic  heart  disease,  emphysema*  asphyxia,  and 
Osier's  disease.  ' 

14.  After  the  transfusion  of  blood. 


V.  BLOOD  PLAQUES. 
If  a  drop  of  fresh  blood  is  examined  microscopically  imme- 
diately after  it  has  been  taken  from  the  body,  a  few  pale,  some- 
what spherical  bodies,  much  smaller  in  size  than  the  erythrocytes, 
may  usually  be  observed.  These  bodies  are  known  as  the  blood 
plaques  or  blood  platelets.  They  are  of  homogeneous  structure, 
either  almost  colorless  or  of  a  pale  yellowish  tint,  spherical  or 
irregularly  ovoid  in  shape,  and  measure  from  1  to  3  or  4  [i  m 
diameter.  They  are  non-nucleated,  and  react  toward  both  basic 
and  acid  anilin  dyes,  having  an  amphophilic  affinity.  Deetjen1  has 

1  Virchow's  Arch.,  1901,  vol.  clxiv,  p.  239. 


BLOOD  PLAQUES. 


I99 


shown  that  the  plaques  exhibit  definite  ameboid  movement — a 
property  denied  these  bodies  by  the  earlier  investigators — and 
that  they  are  apparently  nucleated. 

The  plaques  exist  as  free  bodies  in  the  general  circulation,  but 
directly  after  the  withdrawal  of  the  blood  from  the  vessels  they  show 
a  remarkable  degree  of  viscosity,  by  virtue  of  which  they  tend  to 
adhere  in  racemose  masses,  the  occurrence  of  which  at  or  near  the 
radiating  points  of  the  fibrin  network  has  already  been  described. 
Zeri  and  Amalgia1  found  that  in  malarial  fever  this  agglutination 
of  the  plaques  did  not  occur,  although  it  was  regularly  observed 
in  other  infections,  such  as  pneumonia,  pleurisy,  tuberculosis, 
enteric  fever,  and  the  exanthemata. 

The  belief  of  Bizzozero2  and  of  Hayem,3  that  the  plaques  repre- 
sented a  so-called  "third  corpuscle  "  of  the  blood,  is  not  justified,  for 
it  has  been  proved  that  these  bodies  are  not  distinct  cellular  entities, 
but  rather  debris,  derived  either  from  the  blood  corpuscles  or  from 
the  plasma.  It  is  evident,  from  the  work  of  Arnold,4  Engel,5 
Klebs,6  and  others,  that  at  least  a  large  proportion  of  the  plaques 
are  simply  bits  of  globular  matter  extruded  from  the  erythrocytes, 
and  in  eosin-methylene-blue  films  the  apparent  eruption  of  plaques 
from  the  stroma  of  the  erythrocytes  can  be  readily  demonstrated. 
It  is  possible  that  some  of  the  plaques  are  derived  by  the  disintegra- 
tion of  the  nuclei  of  the  leucocytes  (Lilienf eld ;7  Howell;8  Gibson9); 
and  that  still  others  are  masses  of  precipitated  globulin  (Lowit10). 
Heim11  believes  that  the  plaques  are  nuclear  formations  of  the 
erythrocytes,  and  claims  that  regeneration  of  the  latter  and  in- 
crease in  the  number  of  blood  plaques  progress  pari  passu. 

Ducchesi's  method  of  macroscopically  demonstrating  the 
plaques  is  of  clinical  interest :  A  few  drops  of  blood  are  collected 
in  a  watch-glass,  which  is  gently  rocked  from  side  to  side  for  a  few 
minutes,  and  then  held  up  to  the  light,  showing  the  plaques  as 
groups  of  delicate  white  granules  in  the  stratum  of  blood  next  to 
the  glass. ^  These  granular  masses  appear  within  from  forty  seconds 
to  two  minutes  after  withdrawal  of  the  blood,  and  disappear  as 
coagulation  commences. 

1 II  Policlin.,  1903,  vol.  ix,  p.  485.       2  Virchow's  Arch.,  1882,  vol.  xc,  p.  261. 
Compt.  rend.  Soc.  biol.,  Paris,  1877,  vol.  ii,  p.  85. 

4  Centralbl.  f.  allg.  Path.,  1897,  vol.  viii,  p.  289. 

5  "Leitfaden  zur  klinischen  Untersuchung  des  Blutes,"  2d  ed.,  Berlin,  1002 
P-5i-  ,  ,   y  , 

6  Ziegler's  Beitr.,  1889,  vol.  iv,  p.  528.  ' 

7  Zeitschr.  f.  physiol.  Chem.,  1895,  vol.  xx,  p.  155. 

8  Jour.  Morph.,  1891,  vol.  iv,  p.  57. 

9  Jour.  Anat.  and  Physiol.,  1886,  vol.  xx,  p.  100. 

10  Arch.  f.  mik.  Anat.,  1891,  vol.  lviii,  p.  598. 

11  Deutsch.  med.  Wochenschr.,  1903,  vol.  xxix,  p.  588. 


200      ERYTHROCYTES,  BLOOD  PLAQUES,   AND  HEMOKONIA. 

Exposure  to  the  air  appears  to  cause  an  almost  immediate  dis- 
appearance of  the  plaques  from  the  blood,  and,  therefore,  they  are 
but  seldom  noticed  in  the  blood  film  prepared  by  the  ordinary 
methods.  With  Wright's  stain,  however,  they  are  readily  demon- 
strable in  the  dry  film.  In  studying  the  plaques  in  their  fresh 
state  the  blood  may  be  drawn  directly  through  a  drop  of  Hayem's 
solution  or  a  weak  solution  of  osmic  acid,  the  mixture  of  the  blood 
and  fixative  being  then  placed  upon  a  slide  and  examined  in  the 
usual  manner.    (See  p.  90.) 

The  number  of  plaques  in  normal  blood  varies  within  wide 
limits,  according  to  the  statements  of  different  authorities,  but 
about  300,000  to  the  c.mm.  is  generally  considered  the  normal 
average,  and  from  180,000  to  500,000  the  range  under  physio- 
logical circumstances. 

The  plaques  generally  are  increased  in  pernicious  anemia, 
severe  secondary  anemias,  leukemia,  pneumonia,  arthritis  de- 
formans, myelitis,  tuberculosis,  bubonic  plague,  and  as  the  effect  of 
residence  in  high  altitudes.  They  are  diminished  in  hemophilia, 
purpura,  and  acute  febrile  diseases,  such  as  erysipelas,  typhus 
fever,  and  the  malarial  fevers. 


VI.  HEMOKONIA. 

Miiller 1  has  called  attention  to  the  constant  presence  in  normal 
and  pathological  blood  of  small,  colorless,  refractive  bodies,  of 
spheroidal  or  dumb-bell  shape,  not  larger  than  1  fi  in  diameter. 
These  bodies,  to  which  the  terms  hemokonia  and  blood  dust  have 
been  applied,  are  highly  refractive,  and  possess  active,  limited 
molecular  motility,  but  not  true  ameboid  motion.  They  have 
been  compared  in  appearance  to  fine  fat  droplets,  to  micrococci, 
and  to  granules  derived  from  the  protoplasm  of  the  leucocytes. 
Nothing  is  known  of  their  histological  character  and  significance 
beyond  the  facts  that  they  are  not  concerned  in  the  process  of 
fibrin  formation,  and  that  they  are  not  fatty  bodies,  since  they  are 
neither  stained  by  osmic  acid  nor  dissolved  by  ether.  Both 
Stokes  and  Wegefarth,2  and  Nicholls3  regard  them  as  free  granules 
of  the  neutrophile  and  eosinophile  leucocytes,  and  believe  that 
they  are  probably  concerned  in  the  protective  properties  of  the 
blood  in  immunity.  Stengel4  suggests  that  they  may  be  simply 
the  products  of  fragmentation  of  the  erythrocytes,  such  as  may 

1  Centralbl.  f.  Path.  u.  Bakteriol.,  1896,  vol.  xxv,  p.  529. 

2  Johns  Hopkins  Hosp.  Bull.,  1897,  vol.  viii,  p.  246. 

3  Phila.  Med.  Jour.,  1898,  vol.  i,  p.  387. 

4  "Text-book  of  Pathology,"  4th  ed.,  Philadelphia,  1903,  p.  335. 


HEMOKONIA. 


20I 


be  produced  by  heating  fresh  blood  to  destructive  temperatures, 
when  bits  of  the  corpuscles  are  seen  to  bud  out,  break  off,  and 
float  free  in  the  plasma,  endowed  with  pseudo-ameboid  motility. 

Miiller  found  large  numbers  of  hemokonia  in  a  case  of  Addi- 
son's disease,  but  these  bodies  were  very  scanty  in  a  number  of 
markedly  cachectic  conditions.  Their  occurrence  in  the  blood 
appears  to  carry  no  definite  clinical  significance. 


SECTION  IV. 


THE  LEUCOCYTES. 


SECTION  IV. 
THE  LEUCOCYTES. 


I.  GENERAL  CHARACTERISTICS. 

In  the  fresh,  unstained  blood  film  the  leuco- 
Appearance  cytes  are  recognized  as  pale  nucleated  cells,  the 
in  majority  of  which  are  larger  in  size  than  the 

Fresh  Blood,  erythrocytes,  by  which  they  are  greatly  outnum- 
bered, the  proportion  of  the  former  to  the  latter 
ranging  approximately  between  i  :  450  and  1  :  1200  in  normal 
blood.  The  size  of  the  normal  white  corpuscles  varies  from 
about  7  p.  to  10  or  12  p.  in  diameter,  and  their  shape,  while  in 
the  resting  stage,  is  irregularly  round  or  oval. 

By  careful  .examination  four  different  varieties  of  these  cells 
may  be  distinguished,  the  distinction  between  these  forms  being 
made  more  striking  by  the  addition  of  a  small  quantity  of  a  one 
per  cent,  acetic  acid  solution  to  the  fresh  film.  These  varieties, 
which  are  essentially  the  same  as  those  first  described  by  Schultze, 
in  1865,1  are  as  follows:  (1)  Non-ameboid  cells  about  the  size 
of  the  normal  erythrocyte,  consisting  of  a  pale,  compact,  spher- 
ical nucleus  encircled  by  a  narrow  zone  of  homogeneous  proto- 
plasm. (2)  Ameboid  cells  almost  twice  the  size  of  the  erythro- 
cyte, consisting  of  a  rather  coarsely  meshed  nucleus,  spherical, 
ovoid,  or  indented  in  form,  surrounded  by  a  relatively  large 
amount  of  clear  protoplasm.  The  latter,  is  highly  opaque,  for 
although  it  forms  an  exceedingly  thin  layer  when  spread  out  flat, 
it  effectually  obscures  the  outlines  of  objects  over  which  it  lies — 
as  an  explanation  for  which  characteristic  Kanthack  and  Hardy2 
presume  that  the  cell  matter  is  composed  of  a  colorless  basis 
embedding  immense  numbers  of  minute  vacuoles  filled  with  a 
substance  of  a  different  refractive  index.  (3)  Ameboid  cells  of 
slightly  smaller  size  than  the  second  variety,  consisting  of  a  single 
twisted  nucleus,  or  of  two  or  more  separate  round  or  ovoid  nuclei, 
embedded  in  a  body  of  protoplasm  crowded  with  exceedingly 
delicate,  moderately  refractive  granules.    The  nuclear  network  is 

1  Arch.  f.  mik.  Anat.,  1865,  vol.  i,  p.  1.     2  Jour.  Physiol.,  1894-95,  vol.  xvii,  p.  81.. 

205 


206 


Til  K  LKUCOCYTKS. 


composed  of  chromatin  threads  closely  united  to  form  a  compact, 
lobulated  structure,  and  the.  protoplasm  appears  to  consist  of  a 
transparent  substance,  of  gelatinous  character,  having  a  refractive 
index  but  slightly  below  that  of  the  granules  which  it  contains. 
(4)  Ameboid  cells  containing  a  convoluted  nucleus,  or  several 
spherical  nuclei,  embedded  in  a  protoplasm  filled  with  coarse, 
highly  refractive,  fat-like  granules.  The  nuclear  structure  con- 
sists of  a  coarsely  meshed,  knotted  network,  and  the  protoplasm 
is  much  less  refractive  than  its  granules,  being  clear  and  struc- 
tureless in  appearance. 

Spontaneous  changes  in  the  shape  of  the  larger 
Ameboid  varieties  of  leucocytes  may  be  observed  if  the  slide 
Movement,  is  placed  upon  a  warm  stage  having  a  temper- 
ature of  about  98. 50  F.  During  these  ameboid 
movements  the  shape  of  the  cells  constantly  undergoes  alteration 
by  the  alternate  contraction  and  expansion  of  the  protoplasm. 
Tentacular  processes  reach  out  from  various  portions  of  the 
cell  body,  while  at  other  points  its  surface  becomes  retracted, 
so  that  it  may  appear  as  an  irregular  nucleated  mass  provided 
with  one  or  more  long,  snake-like  arms  projecting  from  a  central 
body.  These  ameboid  cells  are  chiefly  concerned  in  the  process 
of  phagocytosis,  or  the  engulfing  and  destruction  of  micro-organ- 
isms and  other  foreign  matter  which  may  gain  entrance  into 
the  circulating  blood,  and  to  leucocytes  which  exert  this  function 
the  term  phagocyte  has  been  applied.  The  well-known  experi- 
ments of  Metschnikoff  1  have  shown  their  propensity  for  seizing 
upon  and  devouring  pathogenic  bacteria,  such  as  the  anthrax 
bacillus  and  the  erysipelas  streptococcus,  and  further  proof  of 
such  phagocytic  action  may  frequently  be  found  in  the  fragments 
of  other  foreign  matter,  such  as  bits  of  old  blood  clots,  malarial 
pigment,  and  fat  droplets  inclosed  in  their  protoplasm. 

It  has  also  been  suggested  by  Gabritschewsky 2  that  it  may  be 
possible  under  some  circumstances  that  phagocytes  are  capable 
not  only  of  engulfing  solid  bodies,  but  that  they  may  also  imbibe 
liquid  substances,  which  are  thus  rendered  harmless  to  the 
organism,  and  to  this  property,  the  term  pinocytosis  has  been 
given  by  this  author.  Drugs  injected  hypodermically  are  taken 
up  by  phagocytic  cells,  which,  according  to  Labbe,3  not  only 
absorb  and  assimilate  medicaments,  but  perhaps  carry  them,  by 
election,  to  a  specific  lesion  of  the  organism — mercury  to  a  syphil- 
itic nidus,  for  instance.    Iron,  iodin,  arsenic,  mercury,  iodoform, 

1  "L' Inflammation,"  Paris,  1892. 

2  Annal.  de  FInstitut  Pasteur,  1894,  vol.  viii,  p.  673. 
1  3  Presse  med.,  1903,  vol.  ii,  p.  725. 


GENERAL  CHARACTERISTICS. 


207 


and  the  salicylates  are  among  the  drugs  dealt  with  in  this 
manner. 

The  ameboid  property  of  the  leucocytes  is  also  responsible  for 
the  ease  with  which  these  cells  escape  from  the  blood  vessels  into 
the  perivascular  tissues  in  inflammatory  lesions,  and  to  a  less  ex- 
tent in  health.  This  well-known  process  of  diapedesis  is  facili- 
tated by  virtue  of  the  leucocyte's  ability  to  elongate  and  flatten 
out  so  that  it  may  readily  emigrate  through  the  spaces  between 
the  endothelial  cells  of  the  vessel  wall. 

The  identification  of  the  various  forms  of 
Cell        leucocytes  depends  largely  upon  the  presence  or 

Granules,  absence  of  granules  in  their  protoplasm,  and  upon 
the  distinctive  manner  in  which  these  granules 
react  toward  the  acid,  basic,  and  so-called  neutral  solutions  of 
the  anilin  dyes.  By  means  of  this  method  of  "color  analysis" 
Ehrlich  has  provided  a  rational  means  by  which  the  study  of  the 
leucocytes  may  be  undertaken. 

Five  varieties  of  granules,  which  are  designated  by  the  use  of 
the  Greek  letters  a,  (3,  y,  d,  and  e,  may  be  recognized  in  the  cell 
bodies  of  the  leucocytes,  as  follows : 

1.  a- granules  (eosinophile,  oxyphile,  or  coarse  oxyphile  gran- 
ules): Coarse,  spherical  or  ovoid,  highly  refractive  granules  of 
a  peculiar  fat-like  appearance,  showing  a  striking  affinity  for  acid 
stains,  especially  for  eosin.  In  normal  blood  they  occur  only  in 
leucocytes  with  polynuclear  or  polymorphous  nuclei,  but  in  cer- 
tain pathological  conditions  they  may  be  found  in  that  variety  of 
the  leucocyte  known  as  the  eosinophilic  myelocyte. 

2.  fi- granules  (amphophile  granules):  Fine  granules  which 
are  capable  of  reacting  toward  both  acid  and  basic  dyes,  inva- 
riably staining  with  the  former  and  sometimes  with  the  latter,  if 
the  stains  are  used  singly,  while  in  a  mixture  of  the  two  they 
always  react  toward  the  acid  dye.  These  granules  never  occur 
in  normal  blood,  but  in  some  pathological  conditions  a  varying 
proportion  of  the  leucocytes  may  exhibit  amphophilic  reactions 
on  the  part  of  some  of  their  granules. 

3.  r- granules  (mast  cell  or  coarse  basophile  granules):  Very 
coarse  granules,  measuring  from  0.2  to  0.4  fi  in  diameter,  and  pos- 
sessing an  intense  affinity  for  basic  dyes.  If  stained  with  car- 
boltoluidin-blue,  with  thionin,  or  with  alkaline  methylene-blue, 
they  are  colored  a  distinctive  deep  purplish-red.  These  granules 
occur  in  a  form  of  leucocyte  known  as  the  mast  cell,  which  is 
abundant  in  myelogenous  leukemia,  and  is  met  with  occasionally 
in  other  diseases. 

4.  ^-granules  (fine  basophile  granules):  Fine  granules,  stain- 


208 


THE  LEUCOCYTES. 


ing  with  basic  dyes,  and  occurring  under  normal  conditions  in 
leucocytes  having  polymorphous  nuclei.  They  are  most  clearly 
demonstrated  with  such  basic  dyes  as  thionin  or  methylene-blue, 
by  which  they  are  stained  a  deep  blue  color. 

5.  e- granules  (neutrophile  or  fine  oxyphile  granules):  Exceed- 
ingly fine  granules,  formerly  thought  to  have  a  selective  affinity 
for  the  neutral  element  of  a  solution  composed  of  acid  and  basic 
dyes,  but  now  known  to  have,  in  reality,  a  feeble  oxyphilic  ten- 
dency. They  occur  abundantly  in  the  normal  polynuclear 
neutrophile  cells,  and  also  in  several  pathological  forms  of  leuco- 
cytes :  the  myelocyte,  the  small  mononuclear  neutrophile,  and 
the  "small  neutrophilic  pseudolymphocyte." 

But  little  is  known  of  the  real  nature  and  function  of  the  leuco- 
cyte granules,  in  spite  of  their  elaborate  study  by  different  in- 
vestigators. Two 'leading  views,  which  excite  much  controversy, 
to-day  command  attention:  the  hypothesis  of  Ehrlich1  and  the 
bioblastic  theory  of  Altmann.2  Ehrlich  regards  them  as  an 
evidence  of  a  specific  secretory  function  on  the  part  of  the  cells, 
which  under  normal  conditions  contain  but  a  single  variety  of 
granules.  They  are  to  be  considered  as  products  of  cellular 
metabolic  activity,  and  are  destined  to  be  given  off  in  the  vicinity 
of  the  cells,  this  elimination  perhaps  constituting  one  of  the  most 
important  functions  of  the  latter.  Far  from  representing  mere 
waste-products,  as  some  authors  contend,  they  are  in  reality  ele- 
ments of  decided,  although  obscurely  defined,  value  to  the  or- 
ganism. Altmann,  in  his  bioblastic  theory,  considers  cell  granules 
as  definite  biological  entities,  and  believes  that  they  "  serve  as  a 
basis  for  the  explanation  of  the  many  phenomena  of  organic  metab- 
olism." In  summing  up  their  functions  he  remarks  that  "they 
effect  through  oxygen-transmission  both  reductions  and  oxygena- 
tion, and  in  this  manner  accomplish  the  disunions  and  the  syn- 
theses of  the  economy  without  sacrificing  their  own  individuality." 

As  a  rule,  the  cell  granules  are  thought  to  be  relatively  simple 
bodies,  although  their  exact  composition  is  as  yet  undetermined. 
It  has  been  proved  by  Weiss3  and  others  that  they  are  of  albu- 
minous character.  The  eosinophile  granules,  in  which  iron  has 
been  demonstrated  by  Barker4  and  other  observers,  are  more  com- 
plex than  the  other  varieties.  They  are  of  a  higher  histological 
structure,  consisting  of  an  external  limiting  portion  which  may 

1  hoc.  cit. 

2"Ueber  die  Elementarorganismen  und  ihre  Beziehungen  zu  den  Zellen," 
2d  ed.,  Leipsic,  1894. 

3  "  Hematologische  Untersuchungen,"  Vienna,  1896. 

4  Johns  Hopkins  Hosp.  Bull.,  vol.  v,  p.  93. 


CLASSIFICATION. 


209 


be  clearly  differentiated  from  the  central  area.  Hankin  and 
Kanthack1  have  determined  the  fact  that  increased  bactericidal 
power  of  the  blood  is  closely  correlated  with  the  discharge  of 
both  eosinophile  and  neutrophile  granules  into  the  plasma,  and 
the  former  observer2  has  furthermore  shown  that  in  experimental 
infections  there  is  at  the  point  of  the  infection  an  accumulation  of 
cells  containing  eosinophile  granules,  together  with  a  discharge 
of  such  granules  during  the  conflict  of  the  cells  with  the  invading 
micro-organisms. 

In  the  normal  adult  the  number  of  leucocytes 
Normal  Num-  in  the  peripheral  circulation  averages  from  about 
ber.         5000  to  10,000  to  the  c.mm.  of  blood.'  In  the 
majority  of  instances,  in  which  the  influences  of 
physical  factors  are  excluded,  a  count  of  7500  leucocytes  per  c.mm. 
may  be  regarded  as  the  mean  normal  average.   Variations  of  several 
thousand  cells  per  c.mm.  above  and  below  this  number  are  within 
physiological  limits,  and  frequently  occur  because  of  the  extreme 
susceptibility  of  the  leucocytes  to  agencies  causing  such  transient 
fluctuations.    The  following  table,  compiled  from  data  given  by 
Hayem,3  Grawitz,4  and  von  Limbeck,5  shows  the  average  number 
of  leucocytes  determined  by  various  authorities : 

Thoma   8687  per  c.mm. 

Von  Limbeck   8500   "  " 

Rieder  \"\'.Y.'.'.'.'.'.'.7686   "  " 

Boeckman;  Halla  75,,    «  « 

Graeber;  Reinecke   "7242    "  " 

Tumas  -  ....... [.[['.  6200   "  " 

Hayem   6000  «  " 

Average  74o6  « 


II.  CLASSIFICATION. 

Six  distinct -varieties  of  leucocytes  may  be  recognized  in  the 
healthy  adult's  blood  stained  by  the  Romanowsky  method  or  by 
Ehrlich's  stain,  according  to  the  methods  described  in  a  previous 
section.  These  varieties,  together  with  their  normal  relative  per- 
centages and  absolute  number  to  the  c.mm.  of  blood,  are  as  fol- 
lows: 

Variety.  Per  cent.     Number  per  c.mm. 

Small  lymphocytes  20-30  1000-3000 

Large  lymphocytes  and  transitional  forms. . .    4-8  200-800 

Polynuclear  neutrophiles  60-75  3000-7^00 

Eosinophils  0.5-5  25-<oo 

Basophiles,  as  high  as  0.5  25 

1  Centralbl.  f.  Bakt.  u.  Parasit.,  1892,  vol.  xii,  p.  777;  ibid.,  1803,  vol.  xiv,  p.  852. 
\  fc"  ?h>'sioL'  l894-95>  vol.  xvii,  p.  81.  s  Log.  cit. 

Khnische  Pathologie  des  Blutes,"  Berlin,  1896.  5  Loc  cit 

14 


210  THE  LEUCOCYTES. 

With  the  decline  of  life  the  proportion  of  polynuclear  neutro- 
philes  rises,  the  lymphocytic  forms  becoming  correspondingly  less 
numerous.  This"  reversal  of  the  youthful  blood  picture  is,  accord- 
ing to  Dobrovici's  researches,1  most  conspicuous  after  the  sixtieth 

^^he  variations  in  these  numbers  and  percentages,  which  de- 
pend upon  different  physiological  and  pathological  influences,  are 

referred  to  in  other  sections. 

The  lymphocytes,  or  small  lymphocytes,  as 
Small  they  are  commonly  designated  in  contradistinc- 
Lymphocytes.  tion  to  the  large  mononuclear  forms,  are  non- 
granular cells  which  measure  from  about  5  to 
xoAi  in  diameter,  their  average  size  being  that  of  the  normal 
erythrocyte,  or  7.5  M  in  diameter.  The  typical  cell  of  this  class 
consists  of  a  single  round,  deeply  staining  nucleus  surrounded  by 
a  narrow  zone  of  protoplasm,  and  sometimes  provided  with  one 
or  two  pseudo-nucleoli,  situated  eccentrically  upon  he  nuclear 
surface.  The  nucleus  is  so  relatively  large  that  it  almost  com- 
pletely fills  the  cell,  being  its  most  conspicuous  part,  while  the  1 rim 
of  protoplasm  is  usually  so  narrow  and  poorly  defined  that  at  first 
glance  it  may  escape  notice.  These  characteristics-a  relatively 
large  nucleus  and  a  relatively  scanty  amount  of  P™^^-"* 
more  conspicuously  exhibited  in  the  smaller  than  m  the  larger 
forms  of  these  cells.    (Frontispiece,  II,  and  Plate  II,  Figs.  1-4,  17, 

^Bviomanowsky's  method  the  nucleus  stains  purple,  in  which 
a  red  tone  prevails,  and  the  protoplasm  pure  sky-blue.  Occa- 
sionally the  protoplasm  is  stippled  with  a  few  rather  coarse  purple 
or  red  granules.  .  '  i 

In  films  stained  with  simple  eosin  and  methylene-blue  solu- 
tions the  nucleus  shows  a  decided  affinity  for  the  basic  dye,  usually 
staining  dark  blue,  or,  more  rarely,  pale  green  The  protoplasm 
shows  as  a  relatively  narrow  encircling  area  of  deep  blue  color 
which  has  been  likened  in  appearance  to  the  surface  of  ground 
glass;  it  is  much  more  intensely  basic  than  the  nucleus,  which 
fools  pale  by  contrast.  With  Ehrlich's  triple  stain  the  nucleus 
being  rich  in  chromatin,  is  colored  deep  blue  or  purple,  and  the 
protoplasm  is  either  entirely  unstained,  appearing  as  a  narrow 
hyaline  halo  surrounding  the  nucleus,  or  it  is  tinged  a  del  cate 
shade  of  pink  if  it  happens  to  react  toward  the  acid  fuchsm  of  the 

Occasionally  small  lymphocytes  are  encountered  in  which  the 
nucleus  is  atypical  both  in  morphology  and  in  staining  properties. 

1  Sem.  med.,  1904,  vol.  xxxiv,  p.  198. 


CLASSIFICATION.  211 

Thus,  some  cells  contain  a  pale,  almost  hyaline  nucleus,  composed 
of  an  exceedingly  scanty  chromatin  structure  which  reacts  very 
feebly  to  the  basic  dyes;  others  contain  a  deeply  stained,  indented 
or  kidney-shaped  nucleus,  similar  in  shape  to  that  of  the  so-called 
'  transitional"  forms;  while  still  others  are  provided  with  a 
nucleus  which  has  evidently  become  completely  divided,  so  that 
such  a  cell  really  contains  two  distinct  hemispherical  nuclei,  rich 
m  chromatin,  deeply  stained,  and  situated  toward  the  poles  of 
the  cell  body.  These  irregular  forms  of  lymphocytes  occur  both 
m  normal  and  in  pathological  blood,  but  with  much  greater  fre- 
quency m  the  latter,  especially  in  both  forms  of  leukemia. 

The  small  lymphocyte  appears  to  possess  greater  powers  of 
resistance  than  any  other  variety  of  leucocyte.  In  his  studies 
of  necrobiosis  of  the  blood  corpuscles  Bodou1  determined  that 
the  degenerative  changes  first  involved  the  large  mononuclear 
hyaline  cells  regarded  as  myelogenous  in  type;  next,  the  transi- 
tional forms;  next,  the  large  lymphocytes  of  lymphatic  origin- 
next,  the  polynuclear  neutrophiles ;  and  last  of  all  the  small  lym- 
phocytes. 

Under  this  term  it  is  convenient  to  include 
Large       both  the  larger  forms  of  the  true  lymphocyte— 
Lymphocytes,  those  measuring  up  or  more  in  diameter— and 
also  that  variety  of  hyaline  cell  known  as  the 
large  mononuclear  leucocyte.    These  two  forms  of  cells,  although 
they  are  generally  considered  as  distinct  histological  species  one 
bemg  a  true  lymphocyte  and  the  other  probably  a  marrow-bred 
element,  may,  for  practical  purposes,  be  classed  together,  since  it 
is  impracticable  to  differentiate  one  from  the  other  in  the  speci- 
men prepared  for  an  ordinary  clinical  examination.2  (Frontis- 
piece, II,  and  Plate  II,  Figs.  5,  6,  and  19-22.) 

Cells  of  this  type  may  range  in  size  from  11  to  15  ju  or  even 
larger  m  diameter,  and  are  usually  of  round  or  ovoid  shape  ex- 
cept m  an  occasional  cell,  where,  in  consequence  of  the  injury 
received  during  the  preparation  of  the  blood  film,  the  outline 
may  be  exceedingly  irregular  and  deformed.    The  nucleus,  which 

1  Virchow's  Arch.,  1903,  vol.  clxxiii,  p.  485. 
Some  authors,  Ehrlich  himself  among  them,  maintain  that  a  distinction  be 

Thus  in  the  fim  stained  with  methylene-blue,  it  is  held  that  the  true  lymphocyte 
Z IT"  Y^ltS*lze\  P°SSesses  a  h^c  protoplasm  and  nucleus' 

tt  tlf  Stam*nS  *ess  deeP!y  than  the  former;  while  the  large  mononuclear  leuco^ 
than  the  for™  7  ProtoP  as™        n^leus,  the  latter  staining  more  intensely 

than  the  former  These  points  of  difference,  although  they  may  be  distinguished 
in  specimens  stained  by  special  methods,  seem  to  be  too  Lei/  drawr. toS 
their  acceptance  as  reliable  criteria  for  the  identification  of  these  two  graips  of 
cells  in  films  prepared  by  the  technic  adapted  to  routine  clinical  work.      §  ? 


2I2  THE  LEUCOCYTES. 

is  round,  ovoid,  or  somewhat  elongated,  is  generally  situated  to- 
ward the  periphery  of  the  cell  body.  In  most  of  the  cells  the 
amount  of  protoplasm  is  relatively  greater  than  that  of  the  small 
lymphocyte,  but  occasionally  this  peculiarity  cannot  be  distin- 

gU1Whh  Wright's  stain  this  cell  stains  fainter  than,  but  in  other 
respects  like,  the  small  lymphocyte,  save  that  it  occasionally  shows 
a  number  of  coarse  and  fine  red  granules  scattered  through  its 

Pr°Wkhsimple  mixtures  of  a  strong  acid  and  basic  dye,  such  as 
eosin  and  methylene-blue,  the  nuclear  chromatin  stains  a  diffuse- 
sky-blue  tint,  and  the  protoplasm  exhibits  a  more  or  less  decided 
affinity  for  the  basic  element  of  the  staining  fluid.  This  tendency 
is  very  marked  hi  some  cells,  the  protoplasm  of  which  contains 
an  intensely  basic  pseudo-granular  zone  staining  much  deeper 
blue  than  the  rest  of  the  cell  body,  paralleling  the  extreme  periph- 
ery of  the  cell,  and  often  apparently  separated  from  the  nucleus 
by  a  distinct  unstained  area.  In  other  cells  this  basic  affinity  is 
not  so  conspicuous,  their  protoplasm  staining  a  diffuse  purplish 
shade  in  which  a  rose-red  tone  prevails.  # 

The  nucleus,  being  poor  in  chromatin,  stains  pale  blue  with  the 
triple  stain,  and  is  usually  so  delicately  tinted  that  it  is  almost 
invisible;  the  protoplasm  is  faintly  tinged  with  pink  or  with  gray- 
ish-blue, or  it  may  remain  practically  colorless,  showing  merely 
as  an  indefinite  hyaline  area  surrounding  the  nucleus. 

Apparent  extrusion  of  portions  of  the  cell  body  is  not  uncom- 
monly observed,  this  phenomenon  producing  a  peculiar  frayed- 
out  "  ragged  appearance  around  the  periphery  of  the  lympho- 
cyte due  to  the  partial  detachment  of  small  bits  of  the  peripheral 
seam  of  basic  protoplasm,  which  loosely  adhere  to  the  outer 
margin  of  the  cell.  Occasionally  these  small  basic  masses  be- 
come entirely  detached,  and  may  be  seen  lying  free  m  the  plasma, 
alongside  the  cell  of  which  they  were  once  a  part. 

Typical  forms  of  the  large  and  small  lymphocyte,  such  as  are 
seen  in  the  great  majority  of  stained  blood  films,  may  be  dis- 
tinguished without  difficulty,  but  in  some  diseases,  notably  in  the 
lymphatic  variety  of  leukemia,  irregular  forms  of  these  cells  are 
found,  the  size  and  nuclear  characteristics  of  which  are  so  confus- 
ingly atypical  that  it  is  sometimes  futile  to  attempt  the  classification 
of  such  hybrids  into  two  arbitrary  groups,  large  and  small.  Thus 
one  may  meet  with  cells  the  size  of  the  small  lymphocyte,  but  hav- 
ing a  feebly  basic,  eccentric  nucleus  and  a  relatively  large  amount 
of  protoplasm;  and  with  cells  identical  with  the  large  lymphocyte 
except  that  they  possess  a  small,  spherical,  strongly  basic  nucleus. 


CLASSIFICATION.  2I^ 

The  reddish  protoplasmic  granules  of  the  large  lymphocyte,  shown 
by  the  Romanowsky  stain,  serve  here  as  valuable  criteria,  but  these 
granules,  unfortunately,  are  not  always  demonstrable  in  irregular 
cells.  In  attempting  to  differentiate  these  atypical  forms  in  the 
triple  stained  specimen  it  is  safe  to  be  guided  by  the  suggestions 
given  by  Thayer,1  who  is  inclined  to  place  more  emphasis  upon  the 
character  of  the  nucleus  than  upon  the  size  of  the  cell  body  as  a 
whole.  Thus,  in  a  doubtful  mononuclear,  non-granular  cell  in 
which  the  nucleus  is  similar  in  size  and  shape  to  that  of  the  small 
lymphocyte,  regardless  of  its  affinity  for  the  basic  element  of  the 
stain,  the  cell  is  classed  as  a  small  lymphocyte,  until  the  size  of 
such  a  cell  exceeds  that  of  the  polynuclear  neutrophile.  Some 
cells  no  larger  than  the  smallest  lymphocyte  may  be  classed  as 
large  lymphocytes  if  their  nuclei  are  decidedly  ovoid  in  shape 
and  pale  in  color.  In  spite  of  every  precaution,  however,  it 
must  be  admitted  that  in  some  instances  differential  counts  of 
these  two  types  of  cells  must  be  more  or  less  inaccurate,  for  the 
obvious  reason  that  so  much  depends  upon  the  personal  equation. 

The  so-called  transitional  forms  are  cells 
Transitional  which  closely  resemble  the  large  lymphocyte  in 
Forms.       shape  and  in  size,  but  which  differ  from  the  latter 
variety  of  cell  chiefly  in  having  a  nucleus  which, 
instead  of  being  ovoid  in  shape,  is  indented  and  drawn  out  into  the 
form  of  a  crescent  with  rounded  poles,  the  concave  aspect  of  the 
nuclear  figure  lying  toward  the  center  of  the  cell.    In  other  forms 
the  nucleus  may  have  become  molded  into  a  figure  resembling 
an  hour-glass,  which  occupies  the  central  portion  of  the  cell  body, 
not  lying  m  contact  with  its  periphery  at  anV  point.  (Frontispiece, 
II,  and  Plate  II,  Figs.  7,  8,  and  23.)  ' 

With  eosin  and  methylene-blue  the  nucleus  shows  a  moder- 
ately strong  affinity  for  the  basic  dye,  being  colored  much  darker 
blue  than  the  nucleus  of  the  large,  but  distinctly  paler  than  that 
ol  the  small,  lymphocyte;  the  protoplasm  is  stained  a  diffuse 
pale  blue,  m  which  the  pink  tinge  of  the  eosin  conspicuously 
prevails.  With  the  triple  stain  the  nucleus  of  this  cell  is  usually 
stained  somewhat  darker  blue  than  that  of  the  large  lymphocyte, 
and  the  protoplasm  is  either  quite  colorless  or,  perhaps,  slightly 
tinged  a  grayish-blue.  6  y 

.  Inasmuch  as  the  clinical  significance  of  the  transitional  forms 
is  identical  with  that  of  the  large  lymphocytes,  it  is  customary  to 
class  both  forms  together  under  a  single  heading  in  the  percentage 
table  of  the  different  forms  of  leucocytes. 

1  Johns  Hopkins  Hosp.  Reports,  1894,  vol.  iv,  p.  103. 


214 


THE  LEUCOCYTES. 


Polynuclear  neutrophiles  are  cells  which,  as  a 
Polynuclear  general  rule,  measure  about  from  10  to  12  fi  in 
Neutrophiles.  diameter,  although  their  size  may  vary  within 
wide  limits,  some  being  not  much  larger  than 
the  small  lymphocytes,  while  others  are  nearly  twice  this  size. 
(Frontispiece,  III,  and  Plate  II,  Figs.  9-11  and  24-27.)  The 
distinguishing  characteristics  of   these   cells   are   the  ^twisted, 
polymorphous  nature  of  the  nuclei  and  the  so-called  "  neutro- 
philic" reaction  of  the  granules  embedded  in  the  protoplasm. 
The  nucleus  may  be  of  almost  any  shape— elongated,  wreathed, 
lobulated,  horseshoe-shaped,  or  twisted  into  designs  resembling 
various  letters  of  the  alphabet,  such  as  S,  Z,  U,  or  E.  It 
usually  consists  of  several  apparently  separate  masses  of  ir- 
regular shape,  connected  with  each  other  by  delicate  filamentous 
strands  of  chromatin,  which  dip  beneath  the  surface  of  the  pro- 
toplasm, and,  owing  to  the  density  of  the  overlying  granules,  are 
invisible  or  but  dimly  defined  in  the  triple  stained  specimen. 
By  the  use  of  the  simpler  double  stains,  such  as  eosm  and 
methylene-blue,  the  presence  of  these  connecting  chromatin 
threads  may  be  demonstrated  with  great  clearness.    Less  com- 
monly, a  cell  contains  several  small  oval  or  round  nuclei,  which 
are  actually  separated  from  each  other,  complete  division  at  the 
points  of  constriction  having  resulted  in  the  production  of  two  or 
three,  and  in  rarer  instances  even  six  or  seven,  distinct  nuclei. 
The  nuclear  structure  is  rich  in  chromatin,  which  forms  a  dense, 
unevenly  staining  network  possessing  a  marked  affinity  for  the 
various  basic  dyes.    It  stains  dark  blue  or  greenish-blue  with  the 
triple  stain,  and  still  more  intensely  blue  with  eosin  and  methyl- 
ene-blue solutions. 

The  fact  that  the  single,  twisted  type  of  nucleus  predominates 
in  these  cells  has  led  to  the  current  use  of  the  adjective  "poly- 
morphonuclear" as  a  substitute  for  "  polynuclear,"  but  it  is  per- 
fectly obvious  that  both  terms  may  be  used  synonymously,  the 
latter  perhaps  being  preferable,  because  of  its  brevity  and  of  its 
established  vogue.  The  irregularity  of  the  nucleus  is  regarded 
as  a  sign  of  the  ameboid  activity  of  the  cell,  as  first  suggested  by 
Arnold,1  and  not  as  an  indication  of  degeneration,  as  formerly 
believed.  It  has  been  effectually  demonstrated  by  Sherrington 
that  if  such  cells  are  allowed  to  quiet  down  before  they  are  killed, 
their  nuclei  usually  return  to  a  spheroidal  form. 

The  protoplasm  of  the  polynuclear  neutrophile  is  densely  packed 
with  exceedingly  fine,  so-called  neutrophile  granules,  which  stain 

1  Arch.  f.  mik.  Anat.,  1887,  vol.  xxx,  p.  226. 

2  Proc.  Internat.  Congress  of  Physiologists,  Liege,  1892. 


CLASSIFICATION.  215 

lavender  or  purple,  or,  rarely,  pink,  with  Ehrlich's  triacid  mix- 
ture, but  which  are  not  stained  by  simple  solutions  of  eosin  and 
methylene-blue.    With  Wright's  stain  these  granules  are  colored 
reddish-lilac  or  pink.    Kanthack  and  Hardy1  have  shown  that 
these  granules  have  "a  minimal  attraction  for  acid  dyes,  or, 
briefly^  a  minimal  oxyphile  reaction,"  and,  furthermore,  that 
Ehrlich's  neutral  mixture,  by  which  they  are  intensely  stained, 
is  not,  chemically  speaking,  a  neutral  stain,  but,  on  the  contrary,' 
a  powerful  and  exceedingly  differential  acid  dye,  intensely  staining 
oxyphile  granules  of  all  varieties.2    Thus,  having  proved  that 
the  granules  of  the  polynuclear  "  neutrophile "  cell  of  Ehrlich 
display  a  distinct,  although  feeble,  affinity  for  acid  dyes,  and  that 
they  are  unstained  by  basic  and  neutral  dyes,  the  term  "  finely 
granular  oxyphile  cell"  has  been  adopted  by  these  authors  for 
this  variety  of  leucocyte,  the  granules  being  known  as  "finely 
granular  oxyphile"  granules.    It  is  doubtful,  however,  if  the  use 
of  these  unwieldy  terms  will  receive  general  approval,  except  by 
certain  of  the  British  school.    To  designate  a  polynuclear  leuco- 
cyte as  a  " finely  granular  oxyphile  cell"  is  even  more  glaringly 
inappropriate  than  the  use  of  Ehrlich's  term,  "  neutrophile,"  for 
other  varieties  of  leucocytes— i.  e.,  myelocytes  and  "  neutrophilic 
pseudolymphocytes"— may  be  just  as  fittingly  described  by  the 
former  phrase. 

The  granules  are  of  very  small  size  and  of  irregular  wedge- 
or  spike-shape,  never  being  spherical  or  ovoid  in  contour.  They 
are  usually  most  densely  distributed  about  the  periphery  of  the 
cell,  whence  they  gradually  shade  off  toward  the  nucleus,  which 
is  frequently  found  to  be  encircled  by  a  perfectly  hyaline,  non- 
granular zone.  The  granules  are  not  always  confined  to  the  cell 
protoplasm,  being  scattered  over  the  nucleus,  portions  of  which 
may  be  partly  obscured  by  the  overlying  granular  film. 

The  jelly-like  substance  of  the  protoplasm  in  which  the  granules 
are  embedded  appears  to  show  a  slight  affinity  for  acid  dyes,  the 
intensity  of  this  affinity  varying  greatly  in  different  cells.  With 
the  triple  stain  this  reaction  is  evidenced  by  the  variable  depth 
of  fuchsin-colored  undertone  which  may  be  detected  beneath  the 

*  Jour.  Physiol.,  1894,  vol.  xvii,  p.  61. 

2  Reasoning  upon  the  basis  that  eosin  stains  with  most  striking  intensity  in  an 
aqueous  solution,  less  decidedly  in  a  glycerin  solution,  and  even  less  strongly  when 
dissolved  in  strong  alcohol,  these  investigators  distinguish  three  classes  of  oxyphile 
granules,  according  to  the  intensity  of  their  affinity  for  acid  dves,  thus  :  (1)  Those 
which  stain  with  eosin  only  in  aqueous  solutions  or  in  alcoholic  solutions  of  a  per- 
centage  below  60;  (2)  those  which  stain  in  both  aqueous  and  glvcerin  solutions, 
but  not  in  a  strong  alcoholic  solution  (90  to  95  per  cent.)  of  the  dye;  and  (3)  those 
which  stain  with  aqueous,  glycerin,  and  strong  alcoholic  solutions.  They  include 
in  the  first  class  the  neutrophile  and  the  amphophile  granules  of  Ehrlich. 


2l6 


THE  LEUCOCYTES. 


purplish  color  of  the  granules;  while  in  the  specimen  stained 
with  cosin  and  methylene-blue  the  protoplasm  is  tinted  evenly 
the  color  of  eosin. 

These  cells  are  the  most  conspicuous  of  all  the 
Eosinophiles.  leucocytes,  and  may  be  at  once  identified  by  the 
presence  of  a  more  or  less  polymorphous  nucleus 
embedded  in  a  protoplasm  studded  with  coarse,  highly  refractive 
granules  which  have  a  strong  affinity  for  acid  dyes,  such  as  eosin 
and  acid  fuchsin.  (Frontispiece,  V,  and  Plate  II,  Figs.  12,  13, 
28,  and  29.)  Owing  to  the  large  size  of  their  granules  and 
to  their  striking  oxyphilic  reaction,  these  cells  are  also  known  by 
the  term  "  coarsely  granular  oxyphile  cells,"  in  contradistinction 
to  the  "finely  granular  oxyphile  cells"  or  polynuclear  neutrophils 
(Kanthack  and  Hardy).  The  size  of  the  eosinophile  varies  very 
greatly,  but  most  of  them  approximate  the  size  of  the  polynuclear 
neutrophil,  or  are,  perhaps,  a  trifle  smaller.  Their  diameter 
commonly  ranges  from  8  to  1 1  although  occasionally  forms 
not  larger  than  the  normal  erythrocyte  are  to  be  observed.  Their 
shape  is  usually  that  of  an  irregular  sphere  or  oval. 

The  nucleus  may  be  kidney-  or  horseshoe-shaped,  or  twisted 
and  drawn  out  into  an  irregular  mass,  but  it  is  rarely  as  con- 
stricted and  deformed  as  that  of  the  polynuclear  neutrophile.  It 
is  nearly  always  situated  eccentrically,  cells  of  this  variety  with 
centrally  placed  nuclei  being  very  uncommonly  seen.  Occasion- 
ally the  eosinophile  contains  multiple  nuclei,  consisting  of  sev- 
eral oval  or  round  masses  between  which  no  connecting  chro- 
matin threads  can  be  distinguished,  but  usually  such  portions 
of  the  nucleus  are  joined  together  by  extensions  of  chromatin 
running  beneath  the  protoplasm.  The  nucleus  stains  faintly,  in 
comparison  with  that  of  the  polynuclear  neutrophile,  although 
more  intensely  than  that  of  the  large  mononuclear  cell;  it  is  col- 
ored pale  blue  or  greenish-blue  by  the  triple  stain,  and  dark  blue 
by  eosin  and  methylene-blue  mixtures. 

The  granules,  which  are  relatively  large  in  size  and  quite  regu- 
larly spherical  in  shape  (in  contrast  to  the  delicate,  irregularly 
shaped  granules  of  the  polynuclear  neutrophile),  react  strongly 
toward  the  acid  elements  of  the  triple  stain;  some  are  stained 
a  brilliant  fuchsin  color,  some  deep  red,  while  others  are  brown- 
ish-yellow or  copper  color,  or  even  almost  black;  with  mixtures 
of  eosin  and  methylene-blue  they  take  the  brilliant  color  of  eosin. 
There  appears  to  be  a  marked  tendency  on  the  part  of  the  gran- 
ules to  overrun  the  nucleus,  so  that  its  morphology  in  some  cells 
is  almost  indistinguishable.  The  granules  are  also  prone  to  be- 
come readily  detached  from  the  protoplasm,  which  doubtless  ac- 


CLASSIFICATION. 


217 


counts  for  their  uneven,  blotchy  distribution  in  many  cells,  in 
which  densely  packed  granular  areas  alternate  with  open  spaces 
merely  punctuated  here  and  there  with  an  occasional  granule. 

Eosinophils  appear  to  offer  but  feeble  powers  of  resistance 
against  external  influences,  so  that  it  is  common  to  find  these 
cells  so  injured  by  the  process  of  making  the  film  that  the  nu- 
cleus has  escaped  from  the  cell  body,  and  the  granules,  lying 
free  in  the  plasma,  are  scattered  about  it  in  a  cloud.  This  insta^ 
bility  or  "explosive"  character  of  the  eosinophil  is  one  of  its 
most  striking  attributes,  for,  while  observed  now  and  then  in  a 
polynuclear  neutrophile,  it  occurs  with  much  greater  frequency 
in  eosinophiles  than  in  the  latter  type  of  leucocyte. 

The  protoplasm  of  the  cell  may  or  may  not  show  an  affinity  for 
the  anilin  dyes;  usually  it  does  not,  so  that  the  granules  appear 
to  be  embedded  in  a  perfectly  hyaline  substance;  occasionally 
the  protoplasm  is  faintly  stained  by  fuchsin  or  by  eosin.  With 
Wright's  stain  it  frequently  takes  the  color  of  the  basic  dye, 
methylene-blue. 

Basophile  Finely  granular  basophile  cells,  containing 
Cells.  Ehrlich's  ^-granules,  are  occasionally  encountered 
in  normal  blood,  but  with  such  rarity  that  their 
real  significance  is  not  understood.    (Plate  II,  Fig.  31.) 

In  general  morphology  and  size  these  cells  resemble  the  poly- 
nuclear neutrophiles.  The  nucleus  is  invariably  twisted,  and  usu- 
ally ^  consists  of  two  or  three  distinct  lobes  joined  by  thin  chro- 
matin bands;  in  the  stained  specimen  it  is  never  of  round  or  oval 
shape,  but  always  shows  evidences  of  polymorphism.  The  nuclear 
structure  is  composed  of  a  delicate,  scanty  network  of  chromatin, 
and  has  a  moderate  affinity  for  basic  dyes,  staining  dull  blue  with 
the  triple  stain  and  pale  sea-green  with  eosin  and  methylene-blue 
mixtures. 

The  protoplasm  of  the  cell  is  closely  packed  with  fine,  irregu- 
larly shaped  granules  having  an  intensely  basic  reaction;  they 
stain  deep  blue  with  solutions  containing  methylene-blue,  but  are 
not  colored  by  the  triple  stain,  showing  in  films  stained  with 
this  mixture  as  groups  of  dull  white  spots  scattered  through  the 
cell  body.  Wright's  stain  is  most  useful  in  bringing  out  the  char- 
acteristics of  these  granules. 
, Myelocytes,  or  marrow  cells,  are  relatively 
Myelocytes,  large  round  or  oval  cells,  ranging  from  to  to  20 ju 
.  .  or  even  more  in  diameter,  their  average  size 

being  somewhat  larger  than  that  of  the  large  lymphocyte,  which 
they  resemble  m  general  morphology.  (Frontispiece,  V  and  VI, 
and  Plate  II,  Figs.  14-16  and  30.)    The  nucleus  of  the  typ- 


2l8 


THE  LEUCOCYTES. 


ical  myelocyte  is  of  spherical  or  ovoid  shape,  and  is  situated 
eccentrically,  lying  distinctly  toward  one  side  of  the  cell,  so  that 
the  peripheries  of  both  cell  and  nucleus  are  often  closely  adjacent 
for  some  little  distance— usually  for  from  one-third  to  one-half 
of  their  course.  The  nucleus  reacts  feebly  toward  the  basic 
element  of  the  triple  stain,  being  colored  a  pale,  delicate  sky- 
blue  with  this  solution;  it  stains  a  moderately  deep  blue  or  purple 
with  eosin  and  methylene-blue  mixtures,  and  appears  to  be  more 
coarsely  netted  and  deeply  stained  than  in  films  prepared  by  the 
preceding  method. 

In  the  smaller  forms  of  myelocytes  the  nucleus  is  frequently 
found  to  occupy  the  center  of  the  cell  body,  so  that  it  is  surrounded 
on  all  sides  by  a  protoplasmic  zone  of  even  width.  In  some  of 
the  larger  forms  the-  nucleus  may  be  indented  and  molded  along 
one  margin  of  the  cell  body  like  that  of  the  so-called  "transitional" 
leucocyte.  In  rare  instances  actual  division  of  the  nucleus  appears 
to  have  occurred,  so  that  two  separate  nuclei,  each  shaped  like  a 
flattened  hemisphere  and  situated  at  an  extreme  pole  of  the  cell, 
may  be  found.  Such  cells  are  often  mistaken  at  first  glance  for 
polynuclear  neutrophiles,  inasmuch  as  both  forms  of  cells  contain 
multiple  nuclei  and  neutrophile  granules;  but  the  nucleus  of  the 
polynuclear  neutrophile  is  always  more  or  less  twisted  and  of  un- 
dulating surface,  relatively  rich  in  chromatin  and  stained  with 
decided  intensity,  and  rarely  situated  at  the  poles  of  the  cell,  while 
the  nuclear  halves  of  this  type  of  the  myelocyte  are  of  regular  out- 
line and  uniformly  close  to  the  surface  of  the  cell,  relatively  poor 
in  chromatin  and  faintly  stained,  and  invariably  occupy  the  extreme 
poles  of  the  cell  body. 

The  protoplasm  of  the  myelocyte  is  filled  with  fine  neutrophile 
granules,  such  as  occur  in  the  polynuclear  neutrophile;  they  are 
most  densely  distributed  at  the  periphery,  and  grow  appreciably 
less  abundant  as  they  approach  the  nucleus,  which  they  may 
overrun,  spreading  over  its  surface  like  a  thin  veil,  so  that  its 
structure  is  more  or  less  hidden. 

This  one  characteristic— the  presence  of  neutrophile  granules 
in  the  protoplasm— at  once  serves  to  distinguish  the  myelocyte 
from  the  large  lymphocyte,  which  it  may  exactly  resemble  in 
size,  shape,  and  nuclear  structure;  the  importance  of  using  a 
selective  neutrophile  stain  to  differentiate  these  granules  in  speci- 
mens used  for  differential  counting  is  therefore  patent. 

With  Ehrlich's  triple  stain  the  granules  stain  purple  or  lavender, 
exactly  like  those  of  the  polynuclear  neutrophile.  With  Wright's 
solution  the  protoplasm  has  an  undertone  of  light  purple,  broken 
here  and  there  by  indistinct,  darker  granular  areas  of  the  same 


CLASSIFICATION. 


219 


color,  indicating  the  presence  of  basophile  granules,  in  addition  to 
those  of  neutrophil  reaction,  which  show  as  a  delicate  lilac  or 
pink  stippling. 

In  certain  pathological  conditions,  notably  in  myelogenous 
leukemia,  an  occasional  myelocyte  may  be  observed  which  con- 
tains both  fine  neutrophile  and  very  coarse  basophile  granules, 
the  latter  being  precisely  identical  in  size,  shape,  and  tinctorial 
qualities  with  Ehrlich's  r  or  mast  cell  granules.  They  are 
situated  both  in  the  protoplasm  of  the  cell  and  over  the  nucleus, 
and  are,  in  the  author's  experience,  seen  most  clearly  in  specimens 
stained  in  solutions  containing  polychrome  methylene-blue.  The 
basic  granules  show  in  such  preparations  as  a  coarse,  brilliant, 
purple  stippling,  contrasting  vividly  with  the  paler,  eosin-colored 
neutrophile  granules  which  fill  the  body  of  the  cell,  and  with  the 
greenish-blue  color  of  the  nucleus. 

Eosinophilic  myelocytes,  or  myelocytes  with  a  protoplasm  filled 
with  coarse  eosinophile  instead  of  neutrophile  granules,  are 
common  to  several  pathological  conditions,  but  occur  with  es- 
pecial frequency  in  the  myelogenous  variety  of  leukemia  and 
also  in  pernicious  anemia,  to  some  extent.  Such  cells  are  iden- 
tical in  size  and  morphology  of  cell  body  and  nucleus  with  the 
commoner  neutrophilic  myelocytes,  from  which  they  differ  only 
in  containing  eosinophile  granules.  (Frontispiece,  V,  and  Plate 
II,  Figs.  14  and  30.) 

The  normal  habitat  of  the  myelocyte  is  in  the  red  bone  mar- 
row, and  its  presence  in  the  circulating  blood  must  always  be  re- 
garded as  pathological.  At  one  time  regarded  as  practically 
pathognomonic  of  leukemia,  the  myelocyte  is  now  known  to  occur 
in  many  other  conditions,  especially  those  characterized  by  pro- 
found cachexia,  by  marked  anemia,  and  by  increase  in  the  num- 
ber of  leucocytes.  The  occurrence  of  myelocytes  in  the  blood 
in  various  diseases  and  the  clinical  significance  of  these  cells  are 
discussed  in  another  place.    (See  "  Myelemia,"  p.  259.) 

Cells  containing  Ehrlich's  ^-granules,  known 
Mast  Cells,  by  the  term  mast  cells,  or  mastzellen,  are  oc- 
casionally present  in  the  peripheral  circulation, 
as  the  result  of  certain  pathological  influences,  but  are  totally 
foreign  to  the  normal  blood  of  man.  (Frontispiece,  VII,  and  Plate 
II,  Figs.  32-36.)  They  are  very  constantly  found,  generally  in 
considerable  numbers,  in  the  myelogenous  type  of  leukemia,  and 
also  occur,  in  small  percentages,  in  many  cases  of  pernicious 
anemia  and  in  other  grave  blood  disorders. 

The  cells  are  of  spherical  or  ovoid  shape,  and  are  characterized 
by  a  relatively  large,  structureless  nucleus  inclosed  in  an  almost 


220 


THE  LEUCOCYTES. 


indefinable  protoplasm,  and  by  the  presence  of  coarse  basophile 
granules  scattered  irregularly  over  the  surface  of  the  cell — marks 
of  identification  which  remain  unchanged  whatever  the  size  of 
the  cell  may  be.  No  variety  of  cell  found  in  the  blood  exhibits 
wider  ranges  in  size.  The  forms  most  commonly  observed  meas- 
ure approximately  from  9  to  12  ft  in  diameter;  some  have  a  di- 
ameter of  fully  20  or  even  22  but  cells  of  this  extremely  large 
size  are  the  exception  rather  than  the  rule;  others  are  scarcely 
larger  than  the  small  lymphocyte,  being  but  7  or  8  fx  in  diameter, 
and  these  very  small  forms  are  also  uncommon. 

The  nucleus  is  round,  oval,  or  somewhat  lobulated,  and  occu- 
pies the  greater  part  of  the  cell  body,  in  which  it  is  usually  situ- 
ated eccentrically.  Owing  to  the  similarity  in  the  appearance  of 
the  nucleus  and  the  protoplasm  it  is  frequently  impossible  to  de- 
termine the  precise  point  at  which  the  former  structure  begins 
and  the  latter  ends,  so  that,  in  the  stained  specimen,  many  cells 
are  met  with  which  appear  to  consist  simply  of  irregular  groups 
of  granules  clinging  to  a  pale  nucleus,  every  definite  trace  of  the 
cell  body  being  lost.  (Plate  II,  Figs.  35  and  36.)  In  films  stained 
with  Wright's  solution  (which  is,  by  far,  the  most  satisfactory  stain 
for  illustrating  the  finer  morphology  of  these  cells)  the  nucleus  is 
colored  a  beautiful,  iridescent  greenish-blue,  the  tint  of  which 
is  so  extremely  delicate  that  in  many  cells  it  is  barely  perceptible. 
The  staining,  though  faint,  is  even  and  clear,  indicating  a  structure 
almost  totally  devoid  of  chromatin. 

The  granules  are  generally  large  and  coarse,  and  vary  greatly 
in  size  and  in  shape.  Some  are  smaller  than  the  granules  of  the 
eosinophile  cell,  while  others  approach  or  even  slightly  exceed 
0.5  fx  in  diameter.  They  may  be  spherical,  egg-shaped,  or  roughly 
cuboid,  the  latter  form  of  granule  being  exceedingly  common. 
A  single  type  of  granules  is  not  always  found  to  the  exclusion  of 
the  others,  for  one  cell  often  contains  granules  of  every  possible 
variety  of  shape  and  size;  this  peculiarity  is  especially  striking 
in  some  of  the  smaller  forms  of  cells  in  which  extremely  coarse 
egg-shaped  and  smaller  spherical  granules  may  be  distinguished 
clinging  to  the  periphery  of  the  nucleus,  about  which  no  evidence 
of  protoplasm  is  demonstrable.  (Plate  II,  Fig.  36,  and  Frontis- 
piece, VII.)  In  other  forms,  both  large  and  small,  the  large 
spherical  or  ovoid  granules  may  prevail  almost  exclusively. 
(Plate  II,  Figs.  33,  34,  and  35,  and  Frontispiece,  VII.)  The 
distribution  of  the  granules  through  the  cell  follows  no  constant 
rule,  but  it  is  evident  that  a  more  or  less  decided  tendency  exists 
toward  their  collection  near  the  periphery.  They  are  always 
most  densely  distributed  at  this  point,  sometimes  extending  in- 


CLASSIFICATION. 


221 


ward  over  the  nucleus,  which  is  thus  partly  hidden,  and  some- 
times crowded  into  a  limited  zone,  which  coincides  with  the  outer 
boundary  of  the  cell  for  the  greater  part  of  its  extent. 

^  The  granules  of  the  mast  cell  show  an  intense  affinity  for  basic 
anilin  dyes,  toward  which  they  react  metachromatically  in  a 
highly  characteristic  manner.  With  Wright's  solution  they  are 
stained  a  deep  royal  purple  color  in  which  the  red  tone  is  dis- 
tinctly evident,  thus  differing  from  the  granules  of  other  basophile 
cells,  which  are  stained  a  pure  blue  with  this  mixture.  Dr.  H.  F. 
Harris  has  called  the  writer's  attention  to  another  distinctive 
method  of  identifying  these  granules,  by  first  staining  with  carbol- 
toluidin-blue  or  with  thionin,  and  then  by  differentiating  with 
Unna's  glycerin-ether  mixture.  In  specimens  thus  treated  the 
mast  cell  granules  are  of  a  dark  red  color,  while  other  basophile 
granules  stain  blue,  so  that  the  former  must  be  regarded  as  hav- 
ing a  modified  basic  reaction.  They  are  stained  reddish-violet 
with  Ehrlich's  acid  dahlia  solution,  and  deep  blue  with  aqueous 
solution  of  methylene-blue.  They  are  not  stained  by  the  tri- 
acid  mixture,  and  appear  as  coarse,  dull  white  spots  through 
the  cell  body  in  films  stained  with  this  solution.  The  distinc- 
tive ^  manner  in  which  they  react  toward  selective  stains  for 
mucin  has  been  discovered  by  Harris,1  who,  in  view  of  this 
fact,  suggests  that  the  term  mucinoblast  be  applied  to  the  mast 
cell. 

The  author  questions  the  identity  of  these  coarsely  granular 
basophilic  blood  cells  with  the  well-known  mast  cell  of  the  tissues, 
although  most  hematologists  consider  them  identical.  Both' 
it  is  true,  contain  granules  which  tinctorially  and  morpholog- 
ically are  identical,  but  it  is  obviously  impossible  to  determine 
cell  identity  by  criteria  such  as  these.  The  mast  cell  of  the 
tissues  differs  from  that  of  the  blood  in  having  a  nucleus  which  is 
smaller  in  relation  to  the  size  of  the  cell  body,  more  centrally 
situated,  and  richer  in  chromatin,  hence  being  more  deeply  and 
more  unevenly  stained.  The  " explosive"  nature  of  the  tissue 
mast  cell  is  also  usually  more  striking,  for  while  cells  with  this 
tendency  are  met  with  not  infrequently  in  the  blood,  they  seem 
to  be  the  rule  rather  than  the  exception  in  the  tissues,  large 
numbers  of  them  consisting  of  a  nuclear  structure  surrounded  by 
dense  clusters  of  granules,  which  are  frequently  drawn  out  in 
long  tentacular  extensions.  In  view  of  these  differences  it  may  be 
well  to  be  more  specific,  by  designating  the  mast  cell  found  in  the 
blood  as  the  hemic  mast  cell. 

1  Phila.  Med.  Jour.,  1900,  vol.  v,  p.  757. 


222 


THE  LEUCOCYTES. 


This  term  has  been  applied  by  Capps1  to  a 
Mononuclear  form  of  leucocyte  which  he  found  in  certain  cases 
Neutro-      of  general  paralysis  of  the  insane,  its  appearance 
philes.       in  the  blood  having  been  noted  after  apoplecti- 
form attacks  and  preceding  death.    This  cell  is 
as  large  as,  or  larger  than,  the  polynuclear  neutrophil,  contains  a 
round  or  ovoid  nucleus  which  is  deeply  stained  by  basic  dyes, 
and  has  a  protoplasm  thickly  sprinkled  with  fine  neutrophil 
granules.    Capps  suggests  that  the  cell  may  be  a  form  of  leuco- 
cyte of  slightly  more  mature  development  than  the  large  lympho- 
cyte, one  in  which  the  development  of  the  granules  has  preceded 
the  nuclear  changes.    The  close  resemblance  of  these  cells  to 
the  smaller  forms  of  myelocytes,  however,  makes  it  reasonable 
to  class  them  as  such. 

Ehrlich  has  described2  as  a  "small  neutro- 
Neutrophilic  philic  pseudolymphocyte "  a  cell  of  the  same 
Pseudolym-   size  as  that  of  the  small  lymphocyte,  and  char- 
PHOCYTES.     acterized  by  a  relatively  large,  round,  intensely 
basic  nucleus,  surrounded  by  a  narrow  zone  of 
protoplasm  filled  with  neutrophile  granules.    This  cell,  it  is 
maintained,  is  of  very  rare  occurrence,  having  been  found  in  the 
blood  only  in  a  case  of  hemorrhagic  small-pox  and  in  the  exudate 
of  a  recent  pleural  effusion.    Ehrlich  differentiates  it  from  a  myelo- 
cyte by  its  small  size,  deeply  staining  nucleus,  and  scanty  amount 
of  protoplasm,  but  these  points  of  distinction  do  not  appear  con- 
clusive, for  many  of  the  smaller,  " dwarf"  forms  of  myelocytes 
have  similar  characteristics.     It  does  not  appear  unreasonable, 
therefore,  to  regard  this  cell  as  an  exceedingly  small  form  of 
myelocyte,  in  which  the  nucleus  is  relatively  larger  and  richer  m 
chromatin  than  is  the  rule  in  the  larger,  more  typical  varieties. 

These  cells,  first  described  by  Tiirk3  as  '  Rei- 
Reizungs-     zungsformen"  (or,  literally,  "stimulation  forms"), 
formen.      are  said  to  occur  in  the  same  pathological  condi- 
tions in  which  myelocytes  are  found,  but  as  yet 
their  exact  significance  is  undetermined.    They  may  be  found  in 
any  condition  provoking  decided  anemia  or  leucocytosis  and  thus 
causing  active  stimulation  of  the  bone  marrow.    The  writer  has 
seen  such  cells  in  the  blood  of  the  post-typhoid  anemias  of  infancy, 
always  in  association  with  lymphocytosis.    The  size  of  the  cell  is 
usually  midway  between  that  of  the  small  and  large  lymphocyte, 
more  often  approximating  the  size  of  the  former.    The  cell  con- 
tains a  round  nucleus,  deficient  in  chromatin,  often  eccentrically 


1  Amer.  Tour.  Med.  Sci.,  1896,  vol.  cxi,  p.  650.  ,  . 

2  Loc.  cit.        3  "  Klinische  Hamatologie,"  Vienna  and  Leipzig,  1904,  p. 


CLASSIFICATION. 


223 


placed  in  the  cell  body,  and  reacting  with  moderate  intensity  to- 
ward the  basic  dyes.  The  protoplasm  is  non-granular,  and  stains 
purple  with  Wright's  stain  and  intense  brown  with  the  triacid 
mixture.  Ehrlich  suggests  that  this  cell  may  possibly  represent 
an  early  stage  of  the  erythroblast,  but  reasons  for  such  an  inference 
do  not  seem  clear. 

The  chief  points  of  distinction  between  the  different  forms  of 
leucocytes,  as  recognized  in  specimens  stained  with  Wright's 
Romanowsky  mixture,  are  tabulated  below: 


Form  of  Cell. 


Small  lymphocyte. 


Large  mononuclear 
leucocyte  or  large 
lymphocyte. 

Transitional  leuco- 
cyte. 


Polynuclear  neutro- 
phile. 


Eosinophile. 

Basophile. 
Myelocyte. 

Mast  cell. 


Size. 


6  to  9  fi. 
10  to  15  fl. 
10  to  15  fl. 

7.5  to  12  fl. 
7.5  to  12  ft. 

7-5  tO  12  fl. 

10  to  20  fl. 

7  to  22  fl. 


Nucleus. 


Reizungsform.  6  to  15  fi 


Single. 
Round. 

Relatively  large. 
D  ark  blue  or  purple 
Single. 

Round  or  ovoid. 
Relatively  small. 
Very  pale  blue. 
Single. 

Indented,  kidney- 
shaped,  or  cres- 
centic. 

Relatively  small. 

Pale  blue. 

Polymorphous  or 

polynuclear. 
Relatively  small. 
Moderately  dark 

blue. 

Polymorphous  01 

polynuclear. 
Relatively  small. 
Pale  blue. 

Polymorphous. 
Relatively  small. 
Dull  blue. 
Single. 

Round  or  ovoid. 
Relatively  large  or 

small. 
Very  pale  blue. 
Single. 

Round,   ovoid,  or 
slightly  lobulated. 
Relatively  large. 
Very  pale  blue. 
Single. 
Round. 

Relatively  small. 
Deep  blue. 


Protoplasm. 


Relatively  small  amount. 
Occasionally  granular. 
Pale  sky-blue. 

Relatively  large  amount. 
Often  granular. 
Pale  blue. 

Relatively  large  amount. 
Often  granular. 
Pale  blue. 


Relatively  large  amount. 
Contains  fine  lilac  or  pink 

neutrophile  granules. 
Relatively  large  amount. 

Contains  coarse  rose-col- 
ored eosinophile  gran- 
ules. 

Relatively  large  amount. 

Contains  fine  blue  baso- 
phile granules. 

Relatively  large  or  small 
amount. 

Contains  fine  lilac  or  pink 
neutrophile  granules. 

Relatively  small  amount. 

Contains  coarse  royal 
purple  basophile  gran- 
ules. 

Relatively  large  amount. 
Non-granular. 
Intense  lilac  or  purple. 


224 


THE  LEUCOCYTES. 


Two  different  views  are  current  at  the  present 
Origin  and   time  regarding  the  origin  and  development  of  the 

Develop-  leucocytes,  the  first  being  that  of  Ehrlich1  and 
ment.  his  followers,  and  the  second  that  maintained  by 
the  Russian  school,  led  by  Uskow2  and  his  pupils. 

According  to  Ehrlich's  teachings,  the  small  lymphocyte  and 
its  mother-cell,  the  large  lymphocyte,  are  developed  in  the  lym- 
phatic tissues  in  the  various  parts  of  the  body,  wherever  such 
structures  exist.  The  large  mononuclear  leucocytes  and  transi- 
tional forms  are  considered  probably  of  myelogenous  origin. 
The  polynuclear  neutrophiles  are  thought  to  develop  exclusively 
in  the  bone  marrow,  the  great  majority  being  evolved  from  the 
neutrophilic  myelocytes  of  this  tissue,  while  a  very  limited  num- 
ber perhaps  arise  from  the  non-granular  large  mononuclear  cells. 
The  eosinophiles  develop  from  the  eosinophilic  myelocytes  in  the 
bone  marrow,  while  the  basophilic  leucocytes  similarly  have  their 
origin  in  basophilic  marrow  antecedents.  Thus,  it  is  maintained 
that  all  varieties  of  leucocytes  may  be  classed  in  two  distinct 
groups  which  have  separate  origins,  functions,  and  relations. 
The  first  group  consists  of  the  lymphocytes,  large  and  small, 
which  are  produced  solely  by  the  lymphatic  tissues;  and  the 
second  group  includes  the  mononuclear  leucocytes  and  transi- 
tional forms,  the  polynuclear  neutrophiles,  the  eosinophiles,  and 
the  basophiles,  all  of  which  cells  are  produced  exclusively  by  the 
marrow.3  Cellular  reproduction,  except  in  rare  instances,  does 
not  take  place  in  the  circulating  blood  stream.  Labbe4  considers 
that  no  such  distinction  between  lymphoid  and  myeloid  cells  is 
possible  in  early  life,  at  which  period  he  believes  that  all  blood- 
forming  tissues  are  capable  of  producing  both  hyaline  and  granular 
cells.  But  as  adult  life  approaches  the  origin  of  the  lymphocytes 
may  be  traced  to  the  lymphatic  tissue,  and  the  birthplace  of  the 
granular  leucocytes  to  the  bone  marrow. 

The  scheme  devised  by  the  Russian  school  contends  for  the 
continuous  evolution  of  the  leucocyte  from  its  earliest  to  its  most 
mature  stages.  Accordingly,  all  varieties  of  the  leucocyte,  except 
the  basophilic  cells,  of  which  no  account  apparently  is  taken,  are 
but  different  developmental  stages  of  one  and  the  same  cell. 
The  youngest  form  of  leucocyte,  the  small  lymphocyte,  originates 

1  hoc.  cit.  .  .  i    i    tt  i  > 

2  "The  Blood  as  a  Tissue,"  1890  (Russian);  also  series  of  articles  by  Uskow  s 
pupils  in  Arch.  d.  Soc.  biol.,  St.  Petersburg,  1893-97. 

3Muir's  article  on  the  relations  of  the  bone  marrow  to  leucocyte  formation 
(Jour.  Path,  and  Bacterid.,  1901,  vol.  vii,  p.  161)  admirably  discusses  the  natal 
differences  of  the  lymphoid  and  myeloid  cells  of  the  blood. 

*  "Le  Sang,"  Paris,  1902. 


CLASSIFICATION. 


225 


in  the  lymph  glands,  the  lymphocytic  bone  marrow,  and  the 
spleen,  from  which  sources  of  origin  it  reaches  the  circulation. 
The  small  lymphocyte  enlarges  until  it  becomes  identical  in 
appearance  with  the  cell  recognized  as  the  large  lymphocyte,  its 
nucleus  at  this  period  of  its  growth  having  become  somewhat 
less  intensely  basic,  although  the  basic  affinity  shown  by  the  cell 
protoplasm  is  unaltered.    The  large  lymphocyte  in  turn  under- 
goes a  simple  increase  in  size,  its  nucleus  meanwhile  becoming 
progressively  paler  and  its  protoplasm  more  feebly  basic,  until 
it  develops  into  the  large  mononuclear  form.     The  nucleus  of 
the  latter  now  becomes  indented  and  molded  into  a  roughly 
crescentic  figure,  its  nuclear  and  protoplasmic  characteristics  re- 
maining unchanged,  and  the  so-called  transitional  form  thus  origi- 
nates—a type  of  cell  which  is  regarded  as  the  immediate  ante- 
cedent of  the  polynuclear  neutrophile.    During  the  next  stage  of 
development  the  size  of  the  transitional  cell  decreases  and  the 
whole  cell  becomes  ameboid;  the  nucleus  becomes  denser,  more 
basic,  and  polymorphous  or  polynuclear;  while  the  protoplasm 
loses  the  last  trace  of  its  basic  tendency  and  becomes  sprinkled 
with  fine  neutrophile  granules,  until  finally  the  mature  form  of 
leucocyte,  the  polynuclear  neutrophile,  is  fully  developed.  The 
final,  or  " over-ripe,"  stage  of  the  leucocyte  is  represented  by  the 
eosinophile,  which  is  thought  to  be  derived  from  the  polynuclear 
form   by  a  transformation  of    the   latter's    neutrophile  into 
■eosinophile  granules.    It  is  maintained  that  these  transitions 
from  one  form  of  cell  to  the  other  occur  partly  in  the  circulat- 
ing blood  and  partly  in  the  blood-forming  tissues— most  largely 
in  the  latter. 

It  is  beyond  the  province  of  this  book  to  discuss  the  merits 
and  demerits  of  these  two  opposing  views,  but  it  may  be  remarked 
that  Uskow's  theory,  which  up  to  the  advent  of  Ehrlich's  observa- 
tions commanded  general  attention  among  hematologists,  has 
been  generally  supplanted  by  the  latter.  The  investigations  of 
Ehrhch  in  this  direction  constitute  the  only  dependable  means 
by  which  many  of  the  pathological  changes  in  the  leucocytes 
may  be  explained,  and  his  views  may  be  accepted,  on  the  whole, 
as  accurate. 

Disintegration  of  the  leucocytes  occurs  chiefly  in  the  spleen 
and  to  a  less  extent  in  the  liver.  Bain's  perfusion  experiments,1 
of  repeatedly  passing  blood  through  these  organs,  indicate  that 
the  hemolytic  action  of  the  spleen  is  directed  mainly  toward  the 
leucocytes  and  especially  toward  the  polynuclear  neutrophile 
cells.    From  Lewis'  studies2  it  is  to  be  inferred  that  the  hemo- 

1  Jour.  Physiol.,  1903,  vol.  xxix,  p.  352.  *  Ibid.,  1902,  vol.  xxviii,  p.  8. 


225  THE  LEUCOCYTES. 

lymph  glands  have  a  similar  function,  by  virtue  of  their  phago- 
cytic endothelium.  . 

In  a  number  of  diseases  associated  with 
Iodin        anemia  and  with  bacterial  or  chemical  toxemia 
Reaction,     the  protoplasm  of  the  polynuclear  neutrophile 
leucocytes,  and  rarely  of  the  myelocytes  and  baso- 
phils shows  a  more  or  less  marked  affinity  for  iodin,  as  shown  by 
staining  with  a  weak  solution  of  this  metal.    Extracellular  iodm- 
stained  masses  also  are  found  in  both  normal  and  pathological 
blood,  but  they  are  without  significance  unless  m  association  with 
leucocytes  showing  a  similar  reaction.    Some  of  these  extracellular 
iodophile  masses  are  doubtless  bits  of  protoplasm  torn  from  the 
leucocytes;  others  may  be  blood  plaques,  while  some  are  but 

artefacts.  ,  ,  ,  f 

Goldberger  and  Weiss1  recommend  the  following  reagent  lor 

demonstrating  the  iodin  reaction : 

Iodin  

Potassium  iodid  ic£ 

MTx\ndlddrsufficient  gum  arable  (about  50  parts)  to  make  a 
syrupy  mixture. 

With  a  camel's-hair  brush  a  layer  of  this  solution  is  painted 
over  the  surface  of  the  dried,  unfixed  blood  film,  upon  which  it 
is  allowed  to  act  for  from  one  to  five  minutes.  The  excess  is 
then  removed  by  blotting  with  a  bit  of  filter-paper,  and  the  speci- 
men is  mounted  in  cedar  oil.  Or,  as  Wolff 2  advises  Zollikofer  s 
method  may  be  used:  placing  the  fresh  film  for  a  few  minutes 
in  a  stoppered  bottle  containing  crystals  of  pure  10dm.  _ 

In  films  thus  treated  the  iodin  reaction  is  recognized  by  a 
slight  or  intense,  diffuse  brown  coloring  of  the  entire  protoplasm, 
or  by  the  presence  throughout  the  protoplasm  of  numerous  in- 
tensely stained,  reddish-brown  granules,  the  latter  change  being 
the  more  common.  In  normal  blood  the  protoplasm  of  the  leu- 
cocytes is  stained  a  pale  yellow  and  the  nuclei  remain  almost 

COl°TheS  above  reaction,  known  as  iodophilia,  is  constant  in  all 
purulent  conditions,  persisting  as  long  as  the  suppurative  focus 
exists,  its  intensity  appearing  to  bear  no  parallelism  to  the  extent 
of  the  pus  collection.  It  signifies  simply  a  general  toxemia  severe 
enough  to  cause  a  form  of  leucocyte  degeneration,  and^  like 
its  corollary,  leucocytosis,  is  merely  a  symptomatic  sign.  Kammer 
believes  that  the  reaction  depends  upon  three  factors  for  its  pro- 

1  Wien.  klin.  Wochenschr.,  1897,  vol.  x,  p.  601. 

2  Zeitschr.  f.  klin.  Med.,  1904,  vol.  li,  p.  407-  kH 

3  Deutsch.  med.  Wochenschr.,  1899,  vol.  xxv,   p.   235,    also  Berlin,  klin. 
Wochenschr.,  .1899,  vol.  xxxvi,  p.  119. 


CLASSIFICATION. 


227 


duction— pyrexia,  leucocytosis,  and  toxemia— and  that  it  is 
caused  by  the  action  of  some  unknown  chemotactic  substance. 
He  groups  the  iodophile  cells,  according  to  their  grade  of  reac- 
tion, into  three  stages:  diffuse  brownish  staining,  circumscribed 
granulation,  and  complete  metamorphosis. 

The  reaction  is  absent  in  pure  tuberculous  abscesses.    It  is 
present  with  great  ^  constancy  in  puerperal  sepsis  and  in  other 
forms  of  septicemia,  frequently  in  pneumonia,  pulmonary  tuber- 
culosis, and  malignant  disease,  and  occasionally  in  marked  cachexias. 
Hofbauer 1  found  iodophile  granules  in  the  leucocytes  in  all  cases  of 
pernicious  anemia,  their  number  being  greatest  in  the  gravest  cases; 
they  were  also  present  in  severe  forms  of  secondary  anemia  and 
in  leukemia,  but  were  absent  in  chlorosis  and  in  pseudoleukemia. 
This  author  also  observed  numerous  iodin-stained  extracellular 
masses  in  a  case  of  purpura  hcemorrhagica.     Dunn,2  study- 
ing the  iodin  reaction  in  children,  found  it  invariably  present  in 
croupous  and  catarrhal  pneumonia,  influenza,  cerebrospinal  men- 
ingitis, empyema,  and  miscellaneous  purulent  conditions;  the  reac- 
tion was  generally  present  in  enteric  fever  and  in  acute  miliary 
tuberculosis.    Cabot  and  Locke3  obtained  uniformly  positive 
reactions  in  septicemia,  pneumonia,  empyema,  and  suppurative 
appendicitis;  in  serous  pleural  effusions  and  in  catarrhal  appendi- 
citis the  test  was  negative.    In  about  one-half  of  the  cases  of 
enteric  fever  examined  by  these  writers  the  test  was  positive, 
usually  only  in  those  complicated  by  hemorrhage,  perforation' 
furunculosis,  or  lung  lesions.    These  studies  have  been  recently 
substantiated  by  Gulland.4 

Experimentally,  iodophilia  has  been  caused  by  Spezia5  by  the 
subcutaneous  injection  of  peptone,  glucose,  and  olive  oil,  and  the 
sign  has  also  been  noted  by  him  during  the  digestive  leucocytosis 
following  a  hearty  meal.  Kaminer6  produced  iodophilia  in  ani- 
mals by  injecting  cultures  and  toxins  of  the  pneumococcus,  the 
Klebs-Loffler  bacillus,  the  typhoid  bacillus,  and  various  pyogenic 
bacteria;  he  failed  to  cause  it  by  injecting  tetanus  toxin. 

The  practical  value  of  this  test  is  considerable  if  it  is  properly 
interpreted  merely  as  a  symptom.  Its  constancy  in  purulent  condi- 
tions, however  slight  in  extent  the  focus  of  pus,  is  useful  in  diagnos- 
ing a  deep-seated  abscess,  if  other  causes  which  also  may  give  rise 
to  the  reaction  can  be  ruled  out.    The  sign  is  also  a  valuable  aid  in 

*  Centralbl.  f.  inn.  Med.,  1900,  vol.  xxi,  p.  1^3. 
Boston  Med.  and  Surg.  Jour.,  1903,  vol.  cxlix,  p.  cu 
Jour.  Med.  Research,  1902,  vol.  vii,  p.  43. 

4  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  880. 

5  Lancet,  1903,  vol.  i,  pp.  655  and  1444. 
Brit.  Med.  Jour.,  1902,  vol.  i,  p.  1049. 


228 


THE  LEUCOCYTES. 


differentiating  serous  from  purulent  effusions  and  inflammations- 
serous  pleurisy  and  empyema;  catarrhal  appendicitis  and  appendic- 
ular abscess.    It  is  also  useful,  according  to  Sorochowitscn,  m  dit- 
ferentiatine  gonorrheal  and  rheumatic  arthritis,  since  positive  reac- 
tions occur"  in  the  former  and  negative  in  the  latter.    The  absence  of 
the  iodin  reaction  in  pure  tuberculous  abscess  and  its  presence  m  all 
other  forms  of  abscess  may  aid  in  distinguishing  between  the  two,  and 
of  ascertaining  whether  a  mixed  infection  exists.    The  persistence 
of  iodophilia  for  forty-eight  hours  or  so  after  a  pneumonia  crisis 
and  after  the  incision  of  a  pus  cavity  suggests,  m  the  first  instance, 
delayed  resolution  or  some  other  post-pneumonic '  complication, 
and,  in  the  second,  imperfect  drainage.    Although  the  writer  has 
followed  out  rather  at  length  the  suggestion  made  by  Hoibauer, 
that  the  intensity  of  the  reaction  serves  as  an  index  to  the  severity 
of  an  anemia,  the  results  from  this  study  have  not  shown  the  relia- 
bility of  such  a  presumption.  .  , 
Neusser,2  in  1894,  described  certain  basic 
Perinuclear  granules  about  the  nuclei  of  the  leucocytes  which 
Basophilia,   he  regarded  as  pathognomonic  of  the  uric  acid 
diathesis,  asserting  that  this  so-called  perinu- 
clear basophilia"  could  be  demonstrated  constantly  in  gout, 
lithiasis,  rheumatism,  leukemia,  and  a  number  of  other  diseases. 
These  statements  were  soon  corroborated  by  Kohsch,  and  tor  a 
time  enjoyed  more  or  less  general  credence.    The  later  researches 
of  Futcher4  and  of  Simon,5  however,  have  entirely  disproved  the 
claims  of  Neusser  and  his  school,  for  these  investigators,  working 
independently,  have  proved  that  perinuclear  basophilia  is  not 
only  quite  uncharacteristic  of  the  uric  acid  diathesis,  but  that  it 
can  be  constantly  demonstrated  in  every  sort  of  blood  whether 
from  healthy  or  from  diseased  persons.    It  is  now  dear  that 
Neusser's  granules  are  simply  artefacts,  due  to  some  slip  in  the 
technic  of  staining.    Ehrlich6  believes  that  their  presence  is  but 
rarely  noted  if  perfectly  pure  crystalline  dyes  are  used  m  pre- 
paring the  stain. 


III.  LEUCOCYTOSIS. 

Leucocytosis  may  be  described  as  an  increase  above  the  normal 
standard  in  the  number  of  leucocytes  in  the  peripheral  blood,  this 

1  Zeitschr.  f.  klin.  Med.,  1904,  vol.  li,  p.  245- 

2  Wien.  klin.  Wochenschr.,  1894,  vol.  vn,  p.  71. 

3  Ibid.,  1895,  vol.  viii,  p.  797-  ... 

4  Johns  Hopkins  Hosp.  Bull.,  1897,  vol.  viu,  p.  85.  fi 

5  Amer.  Jour.  Med.  Sci.,  1899,  vol.  cxvn,  p.  139- 


Plate  in. 


Leucocytosis. 
( Triacid  Stain.) 


^^^^^^ 

Contrast  this  illustration  with  leukemia,  Plates  IV  and  V. 


(E.  F.  Faber, /<?<:.) 


LEUCOCYTOSIS.  22g 

change  either—  (a)  involving  both  an  absolute  and  a  relative  increase 
m  the  polynuclear  neutrophile  cells  with  a  consequent  relative  dimi- 
nution m  the  proportion  of  mononuclear  non-granular  forms  or  (b) 
affecting  all  varieties  of  leucocytes  alike. 

A  leucocytosis  of  the  first  kind,  also  termed  a  polynuclear  neu- 
trophile leucocytosis,  is  by  far  the  more  common  of  the  two  types- 
it  may  be  symptomatic  either  of  pathological  or  of  physiological 
conditions,  being  found  almost  invariably  in  the  former  and  fre- 
quently m  the  latter.  A  leucocytosis  of  the  second  kind,  or  a 
general  increase  unattended  by  any  disturbance  in  the  normal 
relative  proportions  of  the  different  forms  of  cells,  is  compara- 
tively rare:  it  is  more  frequently  dependent  for  its  production 
upon  physiological  than  upon  pathological  factors,  but  it  may 
occur  under  either  of  these  circumstances. 

From  these  facts  it  is  obvious  that  simply  an  increase  in  the 
total  number  of  leucocytes,  without  regard  to  the  differential 
changes  involved,  does  not  of  necessity  constitute  a  leucocytosis 
JNor  is  it  possible  to  recognize  the  condition  with  certainty  by 
any  such  criterion  as  a  deviation  from  the  ratio  of  red  to  white 
cells  maintained  in  health.    To  state  that  a  patient's  blood  con- 
tains, say,  50,000  leucocytes  to  the  c.mm.  suggests  both  leuco- 
cytosis and  leukemia,  but  to  add  to  such  a  statement  the  fact 
that  of  these  50,000  leucocytes  90  per  cent,  are  of  the  polynuclear 
neutrophile  variety,  at  once  stamps  the  condition  as  a  genuine  leu- 
cocytosis.   In  order,  therefore,  to  distinguish  leucocytosis  with 
absolute  certainty  the  character  of  the  leucocytes  involved  in  the 
increase  must  be  determined  by  a  differential  count  of  the  stained 
specimen  of  blood.    (Plate  III.) 

Leucocytosis  may  be  of  a  more  or  less- transient  character,  or 
may  persist  for  a  long  period,  its  duration  being  dependent  upon 
the  nature  of  the  underlying  cause.  In  acute  diseases  it  is  usually 
a  temporary  condition,  but  in  long-continued  affections  it  is  pro- 
longed m  relation  to  the  chronicity  of  the  lesion  by  which  the 
increase  is  excited. 

For  clinical  purposes  all  forms  of  leucocytosis  may  be  classed 
under  two  mam  groups,  physiological  and  pathological  these  be- 
ing further  divided  as  follows : 

Physiological  Leucocytosis. 

1.  Leucocytosis  of  the  new-born. 

2.  Digestion  leucocytosis. 

3.  Leucocytosis  of  pregnancy  and  parturition. 

4.  Leucocytosis  due  to  thermal  and  mechanical  influences 

5.  I  ermmal  leucocytosis. 


23° 


THE  LEUCOCYTES. 


Pathological  Leucocyiosis. 

1.  Inflammatory  and  infectious  leucocytosis. 

2.  Leucocytosis  of  malignant  disease. 

3.  Post-hemorrhagic  leucocytosis. 

4.  Toxic  leucocytosis. 

5.  Experimental  leucocytosis. 


Physiological  Leucocytosis. 

The  leucocytoses  associated  with  a  number  of 
Character,  purely  physiological  conditions  are  generally  of 
brief  duration,  and,  as  a  rule,  involve  a  moderate 
increase  in  the  white  corpuscles,  the  gain  in  many  instances  being 
trifling  and  never  excessive.  As  noted  in  a  preceding  paragraph, 
the  increase  sometimes  affects  equally  all  forms  of  leucocytes,  so 
that  although  the  total  number  of  cells  is  higher  than  the  normal 
standard,  the  relative  percentages  of  the  different  varieties  remain 
in  the  ratio  observed  to  normal  blood.  In  other  instances  the 
gain  is  due  to  an  absolute  and  relative  increase  in  the  polynuclear 
neutrophiles,  with  a  consequent  decrease  in  the  percentage  of 
non-granular,  mononuclear  forms. 

The  increase  of  leucocytes  under  such  condi- 
Causal      tions  is  to  he  regarded  usually  as  a  physical 
Factors.      phenomenon  depending  upon  temporary  concen- 
tration of  the  blood  or  upon  an  unequal  distri- 
bution of  the  cells  in  favor  of  the  peripheral  vessels.  Evidence 
is  wholly  lacking  to  show  that  it  is  caused  by  an  actual  overpro- 
duction of  leucocytes  by  the  blood-forming  organs,  thus  produc- 
ing a  general  increase  through  all  parts  of  the  body.    It  is,  there- 
fore, reasonable  to  believe  that  the  high  leucocyte  counts  may 
be  accounted  for  by  such  factors  as  decrease  in  the  total  volume 
of  blood  plasma,  and  the  transference  of  cells  from  the  vessels 
of  the  deeper  tissues  to  those  of  the  superficial  parts  of  the  body 
1  Leucocytosis  of  the  New-born.-The  blood  of  the  infant  at 
birth  contains  two  or  three  times  the  number  of  leucocytes  found 
in  the  normal  adult,  the  count  usually  ranging  from  15,000 .  to 
20,000  or  higher  during  the  first  forty-eight  hours  of  life.  Alter 
this  time  the  number  of  cells  gradually  decreases  until,  by  tne 
end  of  the  first  or  second  week,  it  has  fallen  to  an  average  of  from 
10,000  to  15,000,  which  figures  may  be  considered  normal  tor 
children  under  one  year  of  age.    In  ten  babies  examined  by  War- 
field1  these  averages  were  found:  first  day,  26,090;  third  day, 

1  Amer.  Med.,  1902,  vol.  iv,  p.  457- 


PHYSIOLOGICAL  LEUCOCYTOSIS.  23I 

13,270;  and  eleventh  day,  15,740  leucocytes  per  c.mm.  In  all 
of  these  cases  it  was  found  that  the  younger  the  infant,  the 
higher  the  count,  which  during  the  first  five  hours  after  birth 
commonly  ranged  between  28,000  and  34,000.  Gundobin1  and 
Carstanjen 2  have  determined,  by  a  series  of  differential  counts,  that 
the  increase  is  due  chiefly  to  an  excessive  gain  in  the  polynuclear 
neutrophils,  the  proportion  of  these  cells  during  the  first  ten  days 
after  birth  averaging  from  60  to  70  per  cent,  of  all  forms  of  leu- 
cocytes. The  extent  of  this  increase  becomes  apparent  when  one 
recalls  the  fact  that  in  the  infant  the  relative  proportion  of  these 
cells  to  the  other  varieties  is  usually  not  more  than  40  per  cent. 
Japha3  considers  42  per  cent,  the  average  of  the  polynuclear  neutro- 
philes in  infants  from  several  weeks  to  twelve  months  of  age. 
By  the  tenth  day  this  polynuclear  increase  usually  subsides,  and 
the  percentage  of  mononuclear  forms  rises  to  the  figure  normal 
at  this  period  of  life.  (See  Section  VI.)  In  prematurely-born 
infants  a  similar  increase  in  the  number  of  leucocytes  is  present, 
but  the  mononuclear  forms  rise  to  their  normal  percentage  more 
rapidly ^than  in  the  full-term  baby;  thus,  in  the  case  of  an  eight- 
months'  child,  examined  by  Whitney  and  Wentworth,4  the  large 
and  small  lymphocytes,  which  averaged  together  but  26  per  cent, 
at  birth,  rose  to  80  per  cent,  by  the  fourth  day,  remaining  at  practi- 
cally this  figure  through  subsequent  counts. 

The  leucocytosis  of  the  new-born  is  probably  attributable 
partly  to  concentration  of  the  blood  by  venous  stasis  and  by  the 
drain  on  the  body-fluids  incident  to  the  early  days  of  life,  and  partly 
to  the  influence  of  digestion  leucocytosis,  which  is  especially  active 
at  this  period.  Schiff 5  first  noted  the  influence  of  the  latter. factor, 
and  particularly  drew  attention  to  the  marked  gain  in  cells  after 
the  baby's  initial  feeding. 

2.  Digestion  Leucocytosis.— -Within  an  hour  after  taking  food 
an  appreciable  increase  in  the  number  of  leucocytes  may  be  ob- 
served in  the  great  majority  of  healthy  individuals,  the  count 
reaching  its  maximum  within  from  two  to  four  hours  after  the 
meal,  and  then  gradually  declining.  Rieder6  estimates  the  aver- 
age increase  at  about  33  per  cent,  in  excess  of  the  normal  figure. 
Meals  rich  in  albuminoids  are  followed  by  a  more  marked  increase 
than  those  consisting  chiefly  of  vegetable  articles  of  diet.  In  in- 
dividuals whose  process  of  digestion  is  slow  from  any  cause  the 
appearance  of  the  leucocytosis  is  also  delayed.    The  following  two 

1  Jahrb.  f.  Kinderheilk.,  1893,  vol.  xxxv,  p.  187. 
\  ^id-'  }9°°>  vol.  Hi,  p.  333.  3  IMd  j  IQOI)  voL  mi 

Cited  by  Rotch,  "  Pediatrics,"  Philadelphia,  1806,  p.  248. 

5  Zeitschr.  f.  Heilk.,  1890,  vol.  xi,  p.  30. 

6  "  Beitrage  zur  Kenntniss  der  Leukocytose,"  Leipsic,  1892. 


232 


THE  LEUCOCYTES. 


instances,  taken  from  von  Limbeck,1  illustrate  the  development  of 
the  leucocytosis  in  the  normal  adult: 


Time. 

Count  of  Leucocytes. 

Time. 

Count  of  Leucocytes. 

ii. 15  A.  M.2 
12.15  p-  M- 

1. 15  P.  M. 
3.15  P.  M. 
5.15  P.  M. 
7.15  P.  M. 

7,600 
6,000 
8,500 
12,000 
14,000 
10,000 

II.30  A.  M.2 
I2.3O  P.  M. 

I.30  P.  M. 

2.30  P.  M. 

3.30  P.  M. 

6.00  P.  M. 

5,800 
10,600 
10,600 
9,600 
6,800 
6,600 

The  gain  is  due  usually  to  a  predominance  of  polynuclear  neu- 
trophile  forms,  with  a  consequent  relative  diminution  in  large  and 
small  lymphocytes;  but  in  some  instances  the  differential  count 
remains  normal,  all  forms  of  cells  sharing  equally  in  the  increase. 

Digestion  leucocytosis  is  not  invariably  present  even  in  those 
who  apparently  enjoy  perfect  health,  its  absence  in  such  instances 
remaining  entirely  unexplained.  It  is  also  absent  occasionally  in 
chronic  constipation,  frequently  in  chronic  gastric  catarrh  and 
anemia,  and  is  found  in  only  a  small  proportion  of  cases  of  gastric 
carcinoma.  Other  lesions  of  the  gastro-intestinal  tract  and  dis- 
eases characterized  by  high-grade  anemia  and  by  marked  de- 
bility may  greatly  delay  or  even  entirely  prevent  the  increase. 
Rieder3  is  authority  for  the  statement  that  digestion  leucocytosis 
does  not  occur  during  pregnancy,  and  Bohland4  finds  that  it  fails 
to  develop  during  the  administration  of  tannic  acid.  Digestion 
leucocytosis  ordinarily  does  not  occur  when  the  leucocytes  are 
already  increased  by  some  pathological  factor. 

In  children,  especially  in  young  breast-fed  infants,  the  increase 
is  very  decided;  in  the  new-born  counts  of  from  30,000  to  35,000 
may  follow  the  first  few  feedings.  (See  Section  VI.)  The  leucocy- 
tosis is  also  marked  after  fasting  and  in  diabetics. 

The  factors  of  digestive  leucocytosis  are,  theoretically,  two- 
fold: the  chemotactic  action  of  the  absorbed  albumins,  which  calls 
from  the  bone  marrow  an  excess  of  polynuclear  neutrophiles ; 
and  the  increased  lymph  flow  from  the  thoracic  duct,  which 
accounts  for  the  lymphocyte  gain.  The  older  writers,  notably  Poll 
and  Hofmeister,5  thought  the  latter  due  to  hyperactivity  of  the 
gastro-intestinal  lymphatic  tissue,  but  this  view  has  been  con- 
troverted by  the  careful  work  of  Goodall,  Gulland,  and  Paton,6  who 
failed  to  find  the  slightest  sign  of  adenoid  proliferation  in  the  walls 

1  Loc.  cit.  2  Meal  of  nitrogenous  and  farinaceous  food. 

3  Loc.  cit.  4  Centralbl.  f.  inn.  Med.,  1899,  vol.  xx,  p.  361. 

5  Cited  by  von  Limbeck,  Joe.  cit. 

6  Jour.  Physiol.,  1903,  vol.  xxx,  p.  1. 


PHYSIOLOGICAL  LEUCOCYTOSIS. 


233 


of  the  gut,  and  who,  furthermore,  found  the  quantitative  and 
qualitative  count  of  leucocytes  identical  in  the  mesenteric  veins  and 
arteries  and  in  £he  general  circulation.  These  investigators  also 
found  that  in  animals  digestion  leucocytosis  is  unaffected  by 
removal  of  the  spleen. 

3.  Leucocytosis  oj  Pregnancy  and  Parturition. —In  the  majority 
of  primiparae  a  moderate  leucocytosis,  not  usually  involving  an  in- 
crease in  excess  of  double  the  normal  count,  is  observed  during 
the  later  months  of  pregnancy.  The  increase  is  less  constant 
and  much  less  marked  in  multiparas,  occurring  in  a  smaller  per- 
centage of  the  latter,  and  amounting  to  a  cellular  gain  of  about 
one-sixth  the  original  count  on  the  average.  The  maximum 
number  of  cells  is  usually  found  immediately  before  and  after  de- 
livery, at  which  time  the  number  of  leucocytes  commonly  rises 
to  about  15,000  per  c.mm.  During  convalescence  the  leucocytosis 
gradually  declines,  and  disappears  before  the  end  of  the  first  week 
after  delivery,  in  uncomplicated  cases.  As  a  general  rule,  in  both 
primiparae  and  in  multiparas  the  degree  of  increase  is  more  decided 
in  young  women  than  in  those  of  middle  age.  It  is  also  marked 
in  the  late  rather  than  in  the  early  stages  of  gestation  and  of  labor. 
The  leucocytosis  of  pregnancy  is  best  explained  by  the  unusually 
active  metabolism  of  this  physiological  period  and  by  the  hyper- 
activity of  the  pelvic  lymph  glands. 

The  careful  blood  studies  by  Hibbard  and  White1  in  55  preg- 
nant women  (33  primiparae  and  22  multiparas)  furnish  the  most 
reliable  data  concerning  the  leucocytosis  of  this  condition.  These 
authors  found  that  leucocytosis  occurred  before  delivery  in  84 
per  cent,  of  primiparae  and  in  75  per  cent,  of  multiparas,  the  aver- 
age counts  in  32  of  the  former  being  15,021  (50  per  cent,  above 
normal)  and  in  20  of  the  latter  11,700  (17  per  cent,  above  nor- 
mal). In  normal  labor  the  number  of  leucocytes  fell  rapidly  after 
delivery,  gradually  reached  the  normal  standard  by  the  fourth  or 
fifth  day,  and  then  again  slowly  rose  until  the  seventh  day,  when 
a  decline  to  normal  was  again  observed.  In  37  cases  at  full  term 
(including  both  primiparae  and  multiparas)  examined  by  J.  Hen- 
derson2 the  leucocyte  count  averaged  21,365,  falling  by  the  tenth 
day  after  labor  to  an  average  of  12,327. 

After  version,  forceps  application,  and  other  operations  the 
leucocytosis  persists  for  a  longer  period.  Post-partum  hemorrhage 
and  lacerations  of  the  genital  tract  may  also  prolong  the  leucocy- 
tosis.   Zangmeister  and  Wagner3  found  that  post-partum  pyrexia 

1  Jour.  Exper.  Med.,  1898,  vol.  iii,  p.  639. 

2  Amer.  Jour.  Obstet.,  1902,  vol.  xlv,  p.  745. 

3  Deutsch.  med.  Wochenschr.,  1903,  vol.  xxviii,  p.  549. 


234 


THE  LEUCOCYTES. 


with  fetid  lochia  is  not  a  factor  of  any  decided  leucocytosis,  such 
as  that  supervening  in  genuine  sepsis.  Pray1  found  in  the  blood 
of  a  woman  delivered  by  Cesarean  section  the  same  leucocyte 
changes  which  accompany  a  normal  labor. 

Differential  counts  in  19  cases  of  Hubbard  and  White's  series 
showed  that  the  leucocytosis  was  of  the  polynuclear  neutrophile 
type,  a  marked  relative  and  absolute  increase  in  these  cells  being 
constantly  present;  as  a  rule,  their  percentage  was  from  85  to  95  of 
all  forms  of  leucocytes,  usually  being  higher  the  higher  the  leu- 
cocytosis. Henderson's  counts  showed  similar  differential  changes. 
These  results  are  unlike  those  obtained  by  Rieder2  and  by  Bjork- 
man,3  the  former  having  stated  that  the  various  forms  of  cells 
remain  practically  normal,  while  the  latter  attributes  the  increase 
to  a  predominance  of  mononuclear  elements. 

Lactation  of  itself  has  no  appreciable  effect  upon  the  leuco- 
cytes, so  that  a  leucocytosis  occurring  in  a  nursing  woman  should 
be  attributed  to  inflammatory  conditions  of  the  breast  or  nipple- 
even  a  mild  mastitis  or  a  slight  irritation  of  the  nipple  may  be 
capable  of  causing  a  prompt  leucocytosis. 

The  number  of  leucocytes  is  somewhat  in  excess  of  normal 
for  a  few  days  preceding  and  during  menstruation  in  the  majority 
of  healthy  women,  according  to  the  investigations  of  Sfameni,4 
but  the  increase  scarcely  ever  reaches  a  degree  which  may  be 
regarded  as  a  genuine  leucocytosis. 

4.  Leucocytosis  Due  to  Thermal  and  Mechanical  Influences. — A 
transient  increase  in  the  number  of  leucocytes  of  the  peripheral 
blood,  not  involving  a  disturbance  of  the  normal  ratio  between  the 
different  forms  of  cells,  is  produced  by  active  local  or  general 
muscular  exercise;^  by  brief  exposure  to  atmospheric  cold;*  by 
cold  baths,  either  local  or  general;7  and  by  the  application  of 
electricity*  and  of  massage.8  The  number  of  leucocytes  is  also 
increased  by  the  effect  of  prolonged  dry  or  moist  heat.9  Hot 
tubbing  likewise  causes  considerable  leucocytosis,10  as  does  free 
sweating,  whether  natural  or  induced.  It  occurred  in  24  of  29 
instances  studied  by  Hannes,11  the  increase  amounting  to  between 

I  Amer.  Gyn.,  1902,  vol.  i,  p.  337.  2  L°c-  ci.L 
3  Amer.  Medico-Surg.  Bull.,  1894,  vol.  vh\  pp.  17  and  79.  Loc.  cit. 
5  Oliver,  loc.  cit.;  Larrabee,  Jour.  Med.  Research,  1902,  vol.  ii,  p.  76;  Schultz, 

Deutsch.  Arch.  f.  klin.  Med.,  1893,  vol.  li,  p.  234;  Willebrand,  Skandin.  Arch, 
f.  klin.  Med.,  1903,  vol.  xiv,  p.  176.  8  Oliver,  loc.  ctt. 

7Winternitz,  Centralbl.  f.  klin.  Med.,  1893,  vol.  xiv,  p.  1017  ;  Thayer, 
Johns  Hopkins  Hosp.  Bull.,  1893,  vol.  iv,  p.  37. 

8  J.  K.  Mitchell,  Amer.  Jour.  Med.  Sci.,  1894,  vol.  evil,  p.  502;  Ekgren, 
Deutsch.  med.  Wochenschr.,  1902,  vol.  xxviii,  p.  519. 

9  Friedlander,  Cong.  f.  inn.  Med.,  Berlin,  1897. 

10  Knapfelmacher,  Wien.  klin.  Wochenschr.,  1893,  vol.  vi,  p.  810. 

II  Centralbl.  f.  inn.  Med.,  1901,  vol.  xxii,  p.  823. 


PHYSIOLOGICAL  LEUKOCYTOSIS. 


235 


3000  and  5000  cells  per  c.mm.  Checking  the  perspiration  resulted 
in  a  fall  of  the  leucocytes  to  normal  within  about  half  an  hour. 

The  increase  under  these  circumstances  is  generally  attributed 
to  blood  concentration  due  to  the  influence  of  increased  vaso- 
motor tension,  whereby  the  liquid  elements  of  the  blood  are  tem- 
porarily decreased,  and,  in  addition,  many  of  the  cells  lodged  in 
the  deeper  tissues  of  the  body  are  swept  into  the  peripheral  cir- 
culation. As  a  rule,  all  varieties  of  leucocytes  share  equally  in 
the  process,  no  single  form  being  unduly  increased  at  the  ex- 
pense of  the  others.  In  the  case  of  long-distance  runners,  how- 
ever, a  very  decided  polynuclear  neutrophile  increase  has  been 
found.1 

5.  Terminal  Leucocytosis. — Terminal  or  preagonal  leucocyto- 
sis  is  the  term  applied  to  an  increase  in  the  number  of  leucocytes 
of  the  peripheral  circulation  frequently  observed  just  before  death. 
It  occurs  during  the  terminal  stages  of  a  number  of  different 
diseases,  and  is  especially  marked  in  those  conditions  in  which 
death  comes  slowly,  being  ushered  in  by  a  more  or  less  mori- 
bund state  of  the  patient,  lasting  for  a  considerable  length  of  time. 
The  increase  is  usually  moderate,  and  the  counts  do  not  often 
exceed  20,000  or  30,000  per  c.mm.,  except  in  those  cases  in 
which  decided  circulatory  embarrassment  has  existed  for  some 
time.  Most  commonly  the  blood  picture  is  one  of  ordinary 
polynuclear  neutrophile  leucocytosis,  although  occasionally  the 
large  and  small  lymphocytes  show  disproportionately  high  per- 
centages, and  still  more  rarely  all  forms  of  cells  may  be  in- 
creased equally.  The  presence  of  myelocytes  in  small  numbers 
is  also  common,  especially  when  the  leucocyte  count  is  high. 

In  pernicious  anemia  the  increase  may  be  so  great  as  to  simu- 
late lymphatic  leukemia,  according  to  Cabot,2  who  found  the  fol- 
lowing blood  changes  on  the  day  of  death  in  this  disease :  ratio  of 
white  to  red  corpuscles,  1  to  15;  and  a  differential  count  of  91.7 
per  cent,  of  lymphocytes,  7.7  per  cent,  of  polynuclear  neutro- 
philes,  and  0.5  per  cent,  of  eosinophiles.  Four  megalob lasts  to 
1000  leucocytes  were  also  found. 

The  following  data  were  obtained  by  the  writer  in  a  case  of 
pernicious  anemia  eighteen  hours  before  death:  hemoglobin,  12 
percent.;  erythrocytes,  622,500  per  c.mm.;  leucocytes,  18,600  per 
cmm.  The  differential  count  of  1000  leucocytes  showed:  lymph- 
ocytes, 46  per  cent.;  polynuclear  neutrophiles,  49.7  per  cent.; 
eosinophiles,  2.3  per  cent.;  myelocytes,  1.6  per  cent.;  and  mast 
cells,  0.4  per  cent.   Megaloblasts  outnumbered  normoblasts  3  to  1, 

1  Cabot,  Blake,  and  Hubbard,  Annals  of  Surg.,  iooi,  vol.  xxxiv,  p.  372. 

2  Loc.  cit. 


236 


THE  LEUCOCYTES. 


24  of  the  former  being  found  in  the  count  of  1000  leucocytes. 
The  number  of  leucocytes  in  four  previous  counts  having  ranged 
from  1000  to  2400  per  c.mm.,  and'  the  proportion  of  lymphocytes 
from  42  to  48  per  cent.,  this  case  illustrates  the  occurrence  of  a 
terminal  leucocytosis  without  a  notable  change  in  the  relative 
percentage  of  different  forms  peculiar  to  the  case  in  question. 

The  principal  cause  of  this  form  of  leucocytosis  is  thought  to 
be  peripheral  stasis  dependent  upon  failure  of  circulatory  com- 
pensation, but  in  many  instances  there  is  good  reason  to  believe 
that  terminal  infections  also  act  as  the  causal  factors. 

Pathological  Leucocytosis. 

Increase  in  the  number  of  leucocytes,  involving 
Occurrence,  chiefly  the  polynuclear  neutrophile  cells  in  the 
great  majority  of  instances,  is  associated  with  a 
wide  variety  of  pathological  conditions,  mainly  inflammatory,  in- 
fectious, and  toxic  in  character,  and  in  such  conditions  the  under- 
lying cause  of  the  phenomenon  is  radically  different  from  that 
which  determines  the  increase  in  physiological  leucocytosis. 
Prominent  examples  of  pathological  lesions  in  which  leucocytoses 
of  this  character  are  observed  are  pneumonia,  diphtheria,  scar- 
let fever,  erysipelas,  rheumatic  fever,  variola,  and  various  septic 
processes.  Enteric  fever,  paratyphoid  fever,  tuberculosis,  typhus 
fever,  Malta  fever,  the  malarial  fevers,  influenza,  measles,  and 
rotheln  are  notable  exceptions,  for  in  these  infections  leucocy- 
tosis occurs  only  as  the  result  of  some  complication. 

The  extent  of  the  leucocytosis,  inasmuch  as  it 
Degree  of  depends  both  upon  the  nature  of  the  exciting  cause 
Increase.  and  upon  the  individual's  reactive  powers,  varies 
within  wide  limits  in  different  cases.  It  is  safe  to 
state,  however,  that  in  the  great  majority  of  instances  the  number  of 
leucocytes  is  rather  below  than  above  20,000  to  the  c.mm.,  counts 
in  excess  of  this  figure  being  noted  in  only  about  one-fourth  of 
the  cases  in  which  the  leucocytes  exceed  the  normal  limits  of 
health.  A  count  of  25,000  cells  per  c.mm.  may  be  regarded  as 
a  decided  leucocytosis,  while  an  increase  of  from  40,000  to  50,000  . 
is  of  extremely  rare  occurrence.  In  an  analysis  of  100  consecu- 
tive counts  made  by  the  writer  in  pathological  conditions,  in  which 
the  number  of  leucocytes  reached  or  exceeded  10,000  per  c.mm., 
it  was  determined  that  the  counts  were  below  20,000  in  65  per 
cent,  of  cases,  and  between  20,000  and  30,000  in  28  per  cent.;  in 
4  per  cent,  the  increase  was  between  30,000  and  40,000;  in  2  per 
cent.,  between  40,000  and  50,000;  and  in  only  one  per  cent,  did  it 


PATHOLOGICAL  LEUCOCYTOSIS.  237 

exceed  50,000.  Judging  from  these  figures,  which,  it  should  be 
remembered,  are  applicable  only  to  the  average  case,  it  appears  to 
be  the  rule  that  in  most  leucocytoses  the  increase  amounts  to 
about  double  the  maximum  normal  number. 

With  rare  exceptions  the  increase  affects 
Differential  chiefly  the  polynuclear  neutrophil  cells,  which 
Changes.  commonly  constitute  at  least  85  per  cent,  of  the 
different  forms  of  leucocytes.  In  many  instances 
the  percentage  is  much  higher,  as,  for  example,  in  a  case  of  sup- 
purative meningitis,  reported  by  Stengel,1  in  which  a  differential 
count  showed  99.5  per  cent,  of  this  variety  of  cells.  The  excep- 
tional cases  in  which  these  disproportionately  high  percentages  of 
polynuclear  neutrophiles  are  sometimes  wanting  are  encountered 
m  the  leucocytoses  of  malignant  disease,  after  hemorrhage,  in  the 
moribund,  and  in  children.  The  relative  lymphocytosis  which  is 
occasionally  observed  under  these  circumstances  is  considered  in 
connection  with  these  conditions.  Coincidentally  with  the  increase 
m  polynuclear  forms  there  is  a  marked  decrease  in  the  relative 
percentages  of  large  and  small  lymphocytes  and  of  eosinophils, 
the  latter  variety  of  cells  sometimes  entirely  disappearing  from 
the  blood.  In  cases  in  which  the  increase  is  marked,  small  num- 
bers of  myelocytes  usually  may  be  observed,  together  with  an 
occasional  cell  whose  characteristics  at  once  suggest  a  stage  of 
development  intermediate  between  that  of  the  myelocyte  and  the 
typical  polynuclear  neutrophile. 

Several  times  the  writer  has  found  in  typical  infectious  leuco- 
cytoses practically  normal  differential  counts,  notwithstanding 
the  high  total  estimates.  Still  rarer  are  those  instances  in  which 
an  inflammatory  or  infectious  lesion  excites  a  high  polynuclear 
neutrophile  percentage  with  no  total  increase  in  the  leucocytes. 
The  latter  blood  change  has  been,  on  insufficient  grounds  in- 
terpreted in  the  same  light  as  a  frank  general  increase. 

The  exact  manner  in  which  pathological  leu- 
Causal      cocytosis  arises  is  a  question  about  which  many 
Factors.      conflicting  views  are  held  by  different  authorities, 
but  the  general  trend  of  opinion  at  the  present 
time  attributes  the  increase  chiefly  to  the  influence  of  chemotaxis. 
According  to  the  chemotactic  theory  of  leucocytosis,  the  pres- 
ence m  the  blood  of  certain  chemical  substances,  produced  by  in- 
fective principles,  is  capable  of  exerting  both  an  attractive  and  a 
repellent  influence  upon  the  ameboid  leucocytes.    If  the  collec- 
tions of  cells  are  attracted  by  such  substances,  the  phenomenon  is 
known  as  positive  chemotaxis,  but  if,  on  the  other  hand,  they  are 

1  Loc.  cit. 


2^g  THE  LEUCOCYTES. 

repelled,  the  condition  is  termed  negative  chemotaxis.  This  mass- 
ing and  repulsion  of  the  leucocytes  may  be  caused  by  various 
agents— by  thermal  and  mechanical  irritants,  by  bits  of  necrotic 
tissue  which  have  gained  entrance  to  the  circulation,  and  espe- 
cially by  the  presence  in  the  blood  of  bacteria  or  of  their  meta- 
bolic products.  Thermotaxis,  or  attraction  by  heat,  may  also 
attract  the  leucocytes  to  an  inflamed  area.  Mendelson1  has  shown 
that  a  local  temperature  of  39°  C.  is  most  active  in  provoking  such 
a  massing  of  the  cells.  In  the  light  of  our  present  knowledge  it 
appears  that  the  different  varieties  of  ameboid  leucocytes  respond 
to  different  kinds  of  chemotactic  influences,  as  an  instance  of  which 
the  behavior  of  the  neutrophiles  and  eosinophiles  to  this  sort  of 
stimulus  may  be  cited.  Certain  substances,  which  for  one  of 
these  groups  of  cells  are  either  positively  or  negatively  chemo- 
tactic, are,  as  a  rule,  indifferent  to  the  other  group,  and  some- 
times even  antagonistic,  for  substances  which  serve  to  attract  one 
group  either  fail  to  influence  or  in  fact  repel  the  other.  Clin- 
ically, this  theory  seems  to  find  corroboration,  for  m  the  great 
majority  of  instances  an  increase  in  either  variety  of  these  cells  is 
associated  with  a  constant  decrease  in  the  other.  In  infections  with 
certain  animal  parasites  this  general  rule  does  not  apply—notably  m 
trichiniasis,  in  ankylostomiasis,  and  in  filariasis,  m  which  it  is  appar- 
ent that  substances  chemotactically  active  for  both  neutrophil  and 
eosinophile  cells  are  at  work.  Ehrlich2  has  shown  that  the  mast  cells 
are  wholly  uninfluenced  by  those  substances  which  exert  a  strong 
chemotactic  influence  upon  the  neutrophiles  and  eosinophiles. 

The  intense  cellular  activity  excited  by  the  en- 
Functions.  trance  of  bacteria  into  the  organism  indicates  an 
attempt  on  the  part  of  the  leucocytes  to  destroy 
the  invading  principle  and  to  counteract  its  noxious  influences. 
In  this  endeavor  it  is  probable  that  in  a  restricted  sense  Metsch- 
nikoff's  hypothesis  holds  true,  and  that  the  immense  numbers  ot 
phagocytic  leucocytes  which  crowd  the  blood  stream  mechan- 
ically engulf  and  destroy  many  of  the  invading  micro-organisms. 
But  of  still  greater  significance  is  the  faculty  which  the  leuco- 
cytes possess  of  producing,  both  by  secretion  and  by  cellular 
disintegration,  certain  chemical  substances  (alexins)  acting  either 
as  directly  bactericidal  or  as  antitoxic  agents.  The  researches  of 
Buchner,3  Lowy  and  Richter,4  Goldscheider  and  Jacob,  and  others 

i  Russkiy  Vrach,  1903,  vol.  ii,  p.  45  abst.  in  Phila.  Med.  Jour.,  1903,  vol.  xi, 
P-  7?5-  a  Arch>  L  Hygi>  l89o,  vol.  xvii,  p.  112. 

^Deutsch.  med.  Wochenschr.,  1895,  vol.  xxix,  p.  240;  also  Virchow's  Arch., 
1898,  vol.  cli,  p.  220. 

5  Zeitschr.  f.  klin.  Med.,  1894,  vol.  xxv,  p.  373- 


PATHOLOGICAL  LEUCOCYTOSIS.  239 

tend  to  show  that  such  substances  either  actually  destroy  the  in- 
fecting micro-organisms,  or  at  least  antidote  and  render  innocuous 
their  poisonous  products.  This  joint  process  of  phagocytosis  and 
bactericidal  action  is  most  intensely  developed  at  the  period  of 
maximum  leucocytosis,  according  to  the  statements  of  Gabri- 
tschewsky.1 

Alexin  is  an  unstable  nucleo-proteid,  acting  as  an  enzyme  and 
corresponding  to  the  complement  of  Ehrlich.  It  is,  according  to 
Metschnikoff,  a  product  of  the  leucocytes,  and  does  not  exist  free 
in  the  blood  plasma.  In  the  process  of  bacteriolysis  the  alexin's 
activity  depends  upon  the  intermediation  of  the  amboceptor  or 
immune  body,  according  to  the  hypothesis  of  immunitv  elaborated 
by  Ehrlich  (p.  151).  The  French  school  holds  that  phagocy- 
tosis is  excited  by  the  action  of  the  amboceptor,  the  chief  source 
of  which  is  also  the  leucocytes.  Metschnikoff  believes  that  the 
functions  of  the  different  phagocytic  cells  in  immunity  are  dis- 
tinctly dissimilar,  the  action  of  the  polynuclear  cells  (or  micro- 
phages)  being  simply  bacteriolytic,  while  that  of  the  large  lympho- 
cytes (or  macrophages)  is  solely  hemolytic. 

It  has  been  suggested  by  Wright  and  Douglas2  that  phago- 
cytosis is  materially  aided  by  the  body  fluids,  which  may  so  influ- 
ence invading  bacteria  as  to  make  them  easy  prey  for  the  phago- 
cytic leucocytes.  They  attribute  this  effect  to  the  presence  in  the 
blood  serum  of  an  unknown  body,  " opsonin,"  which  is  thought 
to  develop  as  immunity  is  established.  In  a  number  of  patients 
suffering  from  furunculosis  Wright  succeeded,  by  treating  them 
with  a  sterile  antistaphylococcus  vaccine,  in  increasing  the  phago- 
cytic power  of  the  blood  which  before  this  treatment  was  dis- 
tinctly below  the  normal. 

In  experimental  leucocytosis,  caused  by  the 
Hypoleucocy-  injection  of  such  irritants  as  bacteria  and  bacterial 
tosis  and  Hy-  products,  organic  extracts,  various  albumins,  and 
perleucocy-  even  by  simple  trauma,  it  has  been  found  that  the 
tosis.        first  effect  of  the  irritant  is  to  cause  a  rapid,  tran- 
sitory diminution  in  the  number  of  leucocytes  in 
the  peripheral  blood,  known  as  hypoleucocy  tosis,  this  decrease 
bemg  succeeded  in  turn  by  an  increase  of  these  cells  in  excess  of 
the  normal  standard,  termed  hy  perleucocy  tosis.    Frequently  in 
simple  traumatic  leucocytoses  after  the  disappearance  of  the  stage 
of  hyperleucocytosis,  the  duration  of  which  is  variable,  Sher- 
rington3 was  able  to  distinguish  a  secondary  stage  of  hypoleuco- 

^Centralbl.  f.  Bakt.  u.  Parasit.,  1898,  vol.  xxiii,  p.  365. 

Proc.  Roy.  Soc,  London,  1903,  vol.  lxxii,  p.  2C7 
3  Ibid.,  London,  1893,  vol.  lv,  p.  161. 


24Q  THE  LEUCOCYTES. 

cytosis  during  which  the  leucocyte  count  again  fell  below  the 

^Within  certain  limits  the  extent  of  this  preliminary  decrease 

and  of  the  subsequent  increase  varies  directly  in  accordance  with 

th fin tensity  of  the  irritant.    If  the  irritant  is  shgh  ,  the  repellent 

nfluence  s  feeble,  and  the  consequent  cellular  increase  is  m- 
intluence  is  leeu ,  that  m  guch  m. 

S^St  ^^  accumulation  of  leucocytes 
at  the  sue  o  the  injection,  without  any  real  increase  m  the  whole 
mass  of  cells     If  the  effects  of  the  irritant  are  severe,  both  the 
Wlent  and  the  attractive  stages  are  promptly  excited  and 
markedly  developed,  and  a  general  increase  in  the  number  of 
kucocvtes  through  the  whole  circulatory  system  promptly  re- 
sult;    If  on       contrary,  the  effects  of  the  irritant  prove  tc ,  be 
"Intense,  the  organism  suffers  a  depression _so ,  prof ound  th  t 
reaction  is  stifled,  and  leucocytosis  does  not  develop.    It  some 
toes  happens  that  the  attractive  influences  of  the  chemotactic 
^p^redominate  over  its  repellent  ^J^^ 
stage  of  hyperleucocytosis  may  develop  without  the  initial  stage 
of  hvooleucocytosis.    Clinically,  the  preliminary  decrease  s  prac- 
ticKever  observed,  perhaps  partly  for  the  reason  last  given 
but  also  in  a  large  measure  because  the  repellent  action  of  the 
San  has  passed  off  by  the  time  the  disease  has  developed  into 
cHnfcal  picture.    In  artificially  excited  leucocytoses  however, 
Ltppeince  is  quite  constant,  for  under  such  fcumstances  th 
irritant  is  introduced  into  the  organism  suddenly  and  m  a  re  a 
tively  massive  dose,  thus  producing  a  decidedly  repellent 

^The  initial  stage  of  decrease  was  termed  the  hucofenic  phase 
bv  Low™  who  attributed  the  change  to  an  actual  destruction  of 
the  leucocytes  or  a  leucocytolysis.  The  subsequent  increase  he 
p^k  of  S  leucocyHc  plafe,  maintaining  that  fatop^ 
tion  of  the  latter  the  preliminary  ^f^^l^ZclX 
in  some  unexplained  manner  essential.  T he  w, ork  of  Gokfecto 
der  and  Jacob2  definitely  proved  the -  error  of  Lowit  s  ^cyt° 
Wtic  hypothesis,  and  demonstrated  the  fact  hat  the  leucopema 

Furthermore,  it  was  also  shown  that  in  some  instances  a  marked 

:  .-Studien  z.  Physiol,  u.  Pathol,  d.  Blutes,"  Jena,  1892.  Loc.  cU. 


PATHOLOGICAL  LEUCOCYTOSIS.  241 

leucocytosis  may  occur  without  the  initial  decrease,  this  being 
the  case  after  the  injection  of  such  substances  as  the  glycerin 
extract  of  spleen.    From  these  experiments  it  seems  reasonable 
to  attribute  the  initial  stage  of  decrease  to  a  repellent  action  of 
the  irritant,  and  to  infer  that  the  stage  of  hyperleucocytosis  is 
(   due  to  an  active  stimulation  of  the  hemogenic  organs  which  results 
certainly  in  an  increased  cellular  output  from,  and  probably  in 
an  increased  cellular  proliferation  in,  this  situation.  Muir's 
investigations1  tend  to  strengthen  this  belief,  and  to  throw 
additional  light  on  the  phenomenon  of  pathological  leucocytosis. 
This  author  found  that  in  experimental  leucocytosis  in  animals, 
produced  by  the  injection  of  pathogenic  bacteria,  changes  occurred 
m  the  bone  marrow,  consisting  of  absorption  of  the  marrow  fat, 
together  with  a  corresponding  hyperplasia  of  the  cells  from  which 
he  believes  the  leucocytes  originate,  many  of  these  cells  under- 
going rapid  multiplication  by  mitosis.    In  inflammatory  leuco- 
cytosis Muir  found  the  following  suggestive  changes:  first,  a  local 
increase  m  the  polynuclear  neutrophile  cells;  second,  an  increase 
of  the  same  variety  of  cells  in  the  circulating  blood;  and  third, 
a  marked  increase  in  the  marrow  of  their  direct  antecedents.  Opie* 
found  in  experimental  bacterial  infections  an  accumulation  of 
eosinophils  at  the  point  of  inoculation,  where  these  cells  undergo 
nuclear  fragmentation  and  other  degenerative  changes  and  thereby 
probably  repel  infection,  although,  unlike  the  polynuclear  neutro- 
phils and  large  mononuclear  leucocytes,  they  rarely  if  ever  act 
as  phagocytes.    Coincident  with  this  massing  of  eosinophils  at 
the  site  of  the  infection  these  cells  are  exceedingly  scanty  in  the 
peripheral  blood,  but  collect  in  large  numbers  in  the  spleen.  Ac- 
cording to  Ehrlich's  latest  views,3  leucocytosis  involving  mainly  an 
increase  of  the  polynuclear  neutrophiles  ("polynuclear  neutrophile 
leucocytosis")  is  the  expression  of  an  independent  chemotactic 
reaction  on  the  part  of  these  cells,  caused  by  the  remote  influence 
of  dissolved  substances  upon  the  bone  marrow,  whereby  this  tissue 
throws  into  the  blood  current  excessive  numbers  of  these  elements. 
_    Schultz4  and  others,  on  the  contrary,  attribute  leucocytosis  en- 
tirely to  changes  in  the  distribution  of  the  cells,  maintaining  that 
increase  m  the  number  of  leucocytes  in  the  peripheral  vessels 
goes  hand  m  hand  with  a  decrease  in  their  number  in  the  vessels 
of  the  internal  organs,  and  vice  versa.    This  view,  however,  has 
been  shown  to  be  untenable. 

vol.  lffifp  Y7e9d'  J°Ur"  l898'  YoL    p'  6°4;  also  Trans>  Path'  Soc"  London>  I9°2> 

\  ^me^T-^ed\ScL'  X9°4>  v°l-  cxxvii,  p.  988.  3  Loc.  cit. 

Tagebl.  der  Naturforsch.  Vers.,  Heidelberg,  1889,  p.  405. 


THE  LEUCOCYTES. 

242 


In  summing  up  the  various  experimental  and  clinical  data  bear- 
■  h    nature  of  the  leucocytoses  associated  with  patho- 

lolcTon Prions  "he  evince  tends  to  confirm  the  view  that  the 
Ze ss  is  in  a  1  nstances,  save  perhaps  those  of  trivial  local  in- 
process  is,  m  throu„hout  the  entire  circulatory  system, 

and  that  it  Ts  systematic  of  an  excessive  output  and  rapid  de^ 
Xtu^le^ytes  by  thebone —  ^  SSX 
i  g^St^WK  ^nevertheless  represents 

the       :sru^  ^is  classy 

included  the  leucocytoses  occurring  during  the  course  of  a  num- 
ber of  leases  of  inflammatory  and  infectious  character,  m  which 

^tot^ -^^^-^  on;he  r? 

of  he  o  ganism  to  overcome  the  noxious  invading  principle,  what- 
nn  fi  is'  nossMe  in  many  instances  to  derive  valuable  cluneal 

iPresse  med.,  1903,  vol.  ii,  p.  725-  Wnred  Wocvtosis  in  wound  in- 

*For  an  account  of  the  practical  va^e  of  induced  [™^y  Hof- 
fections  (reviewing  the  studies  of  Lowy,  R^f!;^  V0L  ii,  p.  1/ 

bauer,  Salieri,  and  Miyake)  ^^^^^^t^",  Paris,  190*. 
3  Presse  med.,  1902,  vol.  11,  p.  107 1,  aiso 


Loc.  cit. 


PATHOLOGICAL  LEUCOCYTOSIS.  243 

the  degree  of  the  increase  is  not  the  extent  of  the  exudate  nor, 
in  all  cases,  its  character,  but  rather  the  systemic  reaction  to  which 
it  gives  rise. 

The  degree  of  leucocytosis  may  be  considered  a  general  index 
to  the  intensity  of  the  infection  and  to  the  strength  of  the  indi- 
vidual's resisting  powers  in  reacting  against  it.  It  follows, 
therefore,  that  intense  infections  occurring  in  individuals  whose 
resisting  powers  are  strong  produce  a  decided  increase;  but 
the  presence  of  an  infection  of  like  intensity  in  one  whose  re- 
sisting powers  are  greatly  crippled  fails  to  cause  leucocytosis,  for 
m  such  an  instance  the  organism  is  so  overpowered  by  the  effects  of 
the  morbid  process  that  it  is  incapable  of  reacting.  The  increase  is 
either  absent  or  slight  when  a  trifling  infection  is  associated  with 
vigorous  resisting  powers,  and  moderate  when  a  moderately  intense 
infection  is  linked  to  fairly  well-developed  resisting  powers. 

The  clinical  inferences  to  be  drawn  from  these  facts  are  of 
value  chiefly  as  corroborative  of  other  well-known  physical  signs 
but  are  obviously  untrustworthy  when  considered  apart  from^the 
latter.    A  marked  leucocytosis  indicates  simply  an  intense  in- 
fection m  a  person  whose  resisting  powers  are  normally  developed 
and  actively  exerted  against  the  disease,  but  it  is  of  no  prognos- 
tic value  m  itself,  for  it  conveys  no  idea  of  the  final  outcome  of 
the  conflict  between  the  disease  and  the  organism.    Absence  of 
leucocytosis  or  a  slight  increase  may  be  either  of  very  favorable 
or  of  very  grave  significance,  inasmuch  as  these  signs  occur  both 
m  trivial  and  m  overwhelming  infections.    If  the  absence  is  asso- 
ciated with  clinical  manifestations  which  point  to  a  severe  infec- 
tion, the  sign  may  be  depended  upon  as  being  of  grave  prognosis 
The  clinical  significance  of  the  leucocytoses  associated  with 
various  inflammatory  and  infectious  processes  will  be  discussed 
m  Section  VII.    A  more  or  less  decided  increase  in  the  num- 
ber of  leucocytes  occurs  with  great  constancy  in  the  following 
groups  of  diseases  of  this  nature : 

I.  General  Infectious  Diseases. 

Actinomycosis.  Pneumonia. 

Asiatic  cholera.  Pyemia. 

Bubonic  plague.  Relapsing  fever. 

Cerebrospinal  meningitis.  Rheumatic  fever. 

Diphtheria.  Scarlet  feven 

Dysentery.  Septicemia. 

^7sl.Pdas-  Spotted  fever  (Montana). 

F^aas.  Syphilis  (secondary). 

Glanders.  Trichiniasis. 

Malignant  endocarditis.  Vaccinia. 

Multiple  neuritis.  Varicella 

Osteomyelitis.  Variola.  ' 

Pertussis.  Yellow  fever. 


244 


THE  LEUCOCYTES. 


II.  Simple  and  Injective  Local  Inflammations. 

Acute  yellow  atrophy  of  the  liver.  Pellagra 


Appendicitis,  catarrhal 
Arthritis,  serous. 
Bronchitis,  acute. 
Burns. 
Cholangitis. 
Cholecystitis.. 
Cystitis. 

Conjunctivitis,  acute. 

Dermatitis. 

Eczema. 

Endocarditis. 

Endometritis. 

Enteritis. 

Epididymitis. 

Gangrene: 

Appendicular.  < 
Cancrum  oris 
Hepatic. 
Pancreatic. 
Pulmonary. 
Gastritis,  acute. 
Gastro-enteritis,  acute. 
Herpes  zoster. 
Hydatid  disease. 
Infected  wounds. 
Mastitis. 
Meningitis. 
Nephritis,  acute. 
Orchitis. 
Ovaritis. 
Pancreatitis. 


Pemphigus. 
Pericarditis. 
Peritonitis. 
Prurigo. 

Purulent  lesions: 

Appendicular  abscess. 
Cerebral  abscess. 
Hepatic  abscess. 
Ischio-rectal  abscess 
Ovarian  abscess. 
Pancreatic  abscess. 
Pelvic  abscess. 
Perinephritic  abscess. 
Prostatic  abscess. 
Pulmonary  abscess. 
Retropharyngeal  abscess. 
Splenic  abscess. 
Superficial  abscess. 
Arthritis,  suppurative. 
Carbuncle. 
Empyema. 
Felon. 
Furuncle. 
Gonorrhea. 

Otitis  media,  suppurative, 
Phlebitis. 
Pyelonephritis. 
Pyonephrosis. 
Pyosalpinx. 
Quinsy. 
Splenitis. 


Under  this  heading  it  is  convenient  to  include  post-oferattve 
leucocytosis,  or  the  increase  commonly  occurring  after  a  surgical 
operation,  as  a  symptom  of  the  normal  process  of  wound  repair 
The  reparative  process,  however,  is  not  always  the  sole  factor  ol 
the  leucocytosis,  since  the  effects  of  the  anesthetic  and  of  hemor- 
rhage also  must  be  taken  into  account.  In  non-septic  uncom- 
plicated cases  the  increase  amounts  to  between  5000  and  10,000 
cells  per  c.mm.  in  excess  of  the  pre-operative  count.  The  maxi- 
mum increase,  which  is  transitory,  is  generally  attained  within 
from  twelve  to  twenty-four  hours,  and  the  normal  standard  is 
again  reached,  by  a  progressive  decline  in  the  leucocyte  count, 
within  two  or  three,  or  at  the  latest  four,  days.  In  uncomplicated 
cases  the  count  falls  to  normal  within  twenty-four  hours  m  Blood- 
good's  experience1;  within  thirty-six  hours  m  Cabot  s  ;  within 
eighty-four  hours  in  Frazier's3;  and  within  five  days  m  C.  Y. 
White's.4    Persistence  of  a  post-operative  leucocytosis  is  signin- 

1  Med.  News,  1901,  vol.  lxxix,  p.  321. 

2  Annals  of  Surg.,  1901,  vol.  xxxiv,  p.  361. 

3  Univ.  of  Pa.  Med.  Bull.,  1901,  vol.  xiv,  p.  363. 
,  4  Univ.  Med.  Mag.,  1900,  vol.  xiii,  p.  260. 


PATHOLOGICAL  LEUCOCYTOSIS.  245 

cant  of  some  such  complication  as  defective  drainage,  infection 
hemorrhage,  or  extensive  inflammation. 

King1  could  determine  no  relation,  in  non-septic  cases,  be- 
tween the  height  of  the  leucocytosis  and  the  ranges  of  the  pulse 
and  temperature.  Frazicr  and  Holloway2  believe  that  the  in- 
crease corresponds  in  general  with  the  extent  of  the  operation 
but  that  it  is  uninfluenced  by  the  degree  of  the  temperature 
and  by  the  anesthesia. 

2.  Leucocytosis  of  Malignant  Disease—A  moderate  leucocy- 
tosis is  commonly,  but  by  no  means  constantly,  associated  with 
the  various  forms  of  carcinomata  and  sarcomata,  but  the  cases  in 
which  no  increase  is  observed  are  even  more  numerous  than  those 
m  which  it  occurs.    It  is  more  common  and  the  increase  is  usually 
regarded  as  more  marked  in  sarcoma  than  in  carcinoma,  but  in 
neither  condition  are  excessively  high  leucocytoses  met  with  fre- 
quently.   In  the  writer's  experience  the  increase,  when  it  does 
occur,  is  generally  moderate  in  most  forms  of  malignant  disease, 
counts  of  less  than  20,000  leucocytes  per  c.mm.  being  the  general 
rule.    Cases  m  which  the  number  of  cells  exceeds  this  figure 
are  comparatively  rare,  but  are  distinctly  more  common  in  sar- 
coma than  in  carcinoma;   it  is  specially  in  rapidly  growing 
neoplasms  of  the  lung,  liver,  and  kidney  that  the  cells  rise  to  30,000 
40,000,  or  even  50,000  or  more.    In  a  series  of  68  consecutive 
cases  of  malignant  disease  in  the  German  and  Jefferson  hospitals 
less  than  one-half  were  accompanied  by  a  leucocyte  count  of 
10,000  or  more,  this  figure  being  reached  or  exceeded  in  approx- 
imately 45  per  cent,  of  cases  of  carcinoma,  while  in  sarcoma  such 
an  increase  was  noted  in  almost  65  per  cent.    Five  per  cent  of 
all  cases  showed  a  high  leucocytosis-that  is,  counts  ranging 
between  30,000  and  50,000.    (For  further  data  concerning  the 
leucocytosis  of  these  conditions  see  "Malignant  Disease,"  Section 

The  behavior  of  the  leucocytes  in  malignant  disease  appears 
ess  contradictory  when  we  inquire  into  the  actual  influence  which 
these  growths  exert  in  provoking  leucocytosis.  It  is  the  cur- 
rent belief  that  malignant  disease  per  se  has  little  if  any  influ- 
ence of  this  sort,  and  that  the  increase,  if  any  occurs,  is  attribu- 
table to  local  inflammatory  complications  and  to  secondary  septic 
infections,  rather  than  to  the  specific  toxic  effects  of  the  neoplasm 
itselt.  In  some  instances  it  is  reasonable  to  suppose  that  the 
profoundly  cachectic  state  of  the  patient  also  is  an  important  de- 
termining factor.    Clinically,  it  is  observed  that  tumors  of  rapid 

2  Amer.  Jour.  Med.  Sci.,  1902,  vol.  cxxiv,  p.  4eo. 
Univ.  of  Pa.  Med.  Bull.,  1901,  vol.  xiv,  p.  363. 


2^(3  THE  LEUCOCYTES. 

development,  involving  a  large  area  of  tissue  and  eomplicated  by 
extensive  metastases,  cause  decided,  often  high,  leucocytoses;  while 
localized  tumors,  of  small  size  and  of  slow  growth,  give  rise  to 
trilling,  if  any,  increase.  Variations  from  this  general  rule  are 
the  result  of  differences  in  the  resisting  powers  of  different  indi- 
viduals, for  the  effects  of  this  factor  in  causing  leucocytosis  are 
potent  in  this  as  in  other  pathological  conditions. 

Qualitatively,  the  leucocytes  usually  show  a  marked  absolute 
and  relative  increase  in  the  polynuclear  neutrophiles,  with  a  con- 
sequent diminution  of  the  mononuclear  forms.  But  in  some  in- 
stances, both  of  carcinoma  and  of  sarcoma,  the  polynuclear  forms 
are  relatively  below  the  normal  percentage,  and  the  lymphocytes 
increased,  so  that  the  blood  picture  is  not  one  of  leucocytosis,  but 
rather  one  of  relative  lymphocytosis;  such  a  change  seems  es- 
pecially prone  to  occur  in  sarcoma  of  the  lymphatic  system,  in 
which  it  may  be  so  marked  that  it  suggests  lymphatic  leukemia. 
There  are  certain  cases  of  malignant  disease  in  which  the  propor- 
tion of  polynuclear  neutrophiles  rises,  although  the  total  number 
of  leucocytes  is  not  increased;  the  polynuclear  gain  is  less  than 
is  usuallv  found  with  high  leucocyte  counts,  and  is  .not 
to  be  regarded  as  of  the  same  significance  as  a  frank  leu- 
cocytosis involving  an  increase  in  the  total  number  of  cells.  (See 
p.  237.) 

The  eosinophiles  are  variously  affected  in  different  cases:  some- 
times they  are  greatly  diminished,  if  not,  indeed,  entirely  absent, 
as  in  most  leucocytoses;  sometimes  they  are  normal;  and  some- 
times they  are  largely  increased  in  number.  The  increase  may 
be  pronounced  in  sarcoma,  this  being  due  probably  to  involve- 
ment of  the  bone  marrow  by  the  growth,  either  directly  or  by 
metastasis. 

Small  numbers  of  myelocytes— 0.5  to  1  or  2  per  cent— are  ex- 
ceedingly common,  being  found  with  great  constancy  in  cases 
with  marked  cachexia,  especially  in  carcinoma.  In  malignant 
disease  involving  the  bone  marrow  the  percentage  of  this  variety 
of  cells  is  much  higher. 

3.  Post-kemorrhagic  Leucocytosis— A  leucocytosis  of  moderate 
grade  commonly  occurs  as  the  result  of  hemorrhage  due  to  trau- 
matism or  to  other  causes.  It  has  been  found  that  in  animals 
the  stage  of  increase  is  preceded  by  a  well-defined  leucopenia, 
which  develops  immediately  after  the  loss  of  blood.  This  initial 
leucopenia,  however,  has  not  yet  been  demonstrated  in  man, 
although  it  probably  occurs.  In  an  extensive  traumatic  hemor- 
rhage the  increase  sometimes  may  be  recognized  in  the  periph- 
eral blood  within  an  hour  after  the  accident,  but  usually  it  is 


PATHOLOGICAL    LKLCOCN  TOS1S. 


247 


not  distinguishable  until  after  the  lapse  of  a  longer  period— from 
five  to  ten  hours,  as  nearly  as  can  be  ascertained.    In  hemor- 
rhage accompanying  various  pathological  conditions,  such,  for 
example,  as  gastric  ulcer,  lung  tuberculosis,  or  uterine  disease, 
the  appearance  of  the  leucocytosis  is  less  prompt  than  in  hemor- 
rhage from  trauma.    The  maximum  increase  is  usually  within 
moderate  limits — approximately  two  or  three  times  the  normal 
standard.    The  injection  of  a  salt  solution  decidedly  aggravates 
the  leucocytosis.    As  an  illustration  of  the  degree  of  leucocytosis 
which  is  commonly  encountered,  Rieder1  noted  in  four  cases 
(hematemesis  from  gastric  ulcer,  fatal  hemophilia,  and  uterine 
hemorrhage)  an  average  count  of  22,625,  tne  maximum  being 
32,600,  and  the  minimum,  15,100.    Inasmuch  as  the  height  of 
the  increase  is  thought  to  correspond  to  the  strength  of  the  organ- 
ism's reaction  in  compensating  the  blood  loss,  it  varies  in  different 
cases.    In  two  individuals  of  equally  strong  regenerative  powers 
a  severe  hemorrhage  will  produce  a  greater  leucocytosis  than  a 
slight  one.    The  duration  of  the  increase  also  varies  with  the 
individual  case,  for  it  depends  upon  a  similar  factor;  but  in  the 
majority  of  instances  it  does  not  last  for  more  than  three  or  four 
days,  according  to  the  investigations  of  Lyon.2  Leucocytoses 
excited  by  traumatic  hemorrhage  are  prone  to  persist  longer  than 
those  due  to  other  causes,  and  the  long-persisting  increases  which 
are  sometimes  associated  with  other  pathological  lesions  should 
be  attributed  to  factors  other  than  the  actual  loss  of  blood.  In 
an  instance  of  leucocytosis  following  venesection  Rieder3  found 
that  the  increase  persisted  for  twelve  days.    Head4  found  that 
in  dogs  the  leucocytosis  following  extensive  hemorrhage  lasted 
for  at  least  seven  days. 

Usually  the  qualitative  changes  involve  chiefly  the  polynu- 
clear  neutrophiles,  which  are  greatly  increased  at  the  expense  of  the 
other  forms  of  cells,  but  in  an  occasional  instance  it  will  be  found 
that  the  mononuclear  varieties  are  greatly  in  excess  of  their  normal 
percentages,  so  that  a  lymphocytosis  is  observed.  Myelocytes 
may  also  be  found  in  considerable  numbers  in  many  cases. 

4.  Toxic  Leucocytosis. — Typical  examples  of  toxic  leucocytosis 
are  found  in  poisoning  by  ptomains  and  by  coal-gas,  in  both  of 
which  conditions  the  predominant  influence  of  a  toxic  agency  in 
producing  the  increase  is  self-evident.  For  the  same  reason|the 
leucocytoses  occurring  as  the  result  of  ether  and  chloroform  'nar- 
cosis, and  in  convulsions  and  acute  delirium,  are  included  in  this 
classification.    In  certain  diseases,  notably  in  the  uric  acid  diath- 

*  L°c-  city  2  Virchow's  Arch.,  1881,  vol.  lxxxiv,  p.  207. 

Loc.  cit.  4  Jour.  Amer.  Med.  Assoc.,  1901,  vol.  xxxvii,  p.  501. 


248 


THE  LEUCOCYTES. 


esis,  in  cholemia,  and  in  uremia,  the  presence  in  the  blood  of 
toxic  principles  is  thought  to  be  the  underlying  factor  of  the  in- 
crease; the  same  probably  is  true  of  a  number  of  other  diseases, 
which,  for  obvious  reasons,  have  been  classed  with  the  infectious 
and  inflammatory  leucocytoses. 

■The  effect  of  gas- poisoning  is  well  illustrated  by  the  blood 
examination  of  a  patient  admitted  to  the  German  Hospital, 
fatally  poisoned  by  illuminating-gas.  The  leucocytes  were  in- 
creased to  32,000  per  c.mm.,  the  gain  being  due  to  an  excessive 
predominance  of  polynuclear  neutrophiles,  as  determined  by  the 
following  differential  count:  small  lymphocytes,  3.5  per  cent.; 
large  lymphocytes,  2.5  per  cent.;  polynuclear  neutrophiles,  92 
per  cent.;  eosinophiles,  0.5  per  cent.;  and  myelocytes,  1.5  per 
cent.  To  what  extent  this  increase  depended  upon  the  actual 
toxic  effects  of  the  gas  and  to  what  extent  it  was  attributable 
to  peripheral  stasis  (which  was  marked  in  this  patient)  are  con- 
jectural. 

The  leucocytosis  caused  by  ether  narcosis  has  been  exhaus- 
tively studied  by  von  Lerber1  and  by  Chadbourne.2  The  inves- 
tigations of  von  Lerber  included  101  cases,  of  which  number  leu- 
cocytosis was  found  in  more  than  95  per  cent.,  the  increase  fre- 
quently amounting  to  two  or  three  times  the  original  count;  in 
the  majority  of  instances  the  maximum  count  was  observed  sev- 
eral hours  after  the  anesthesia  was  produced.  Chadbourne  has 
carefully  studied  21  cases,  all  of  which  showed  a  more  or  less 
decided  leucocytosis,  the  minimum  gain  being  6  per  cent.,  the 
maximum  73  per  cent.,  and  the  average  37.3  per  cent.  He  found 
that  the  leucocytosis  developed  most  rapidly  during  the  early 
part  of  the  etherization,  and  that  only  exceptionally  did  it  persist 
for  more  than  twenty-four  hours.  Differential  counts  in  five 
cases  showed  that  all  forms  of  cells  were  proportionately  in- 
creased. This  author  attributes  the  increase  to  the  irritating 
effects  of  the  ether  vapor  upon  the  mucous  membrane  of  the 
respiratory  tract.  J.  Chalmers  Da  Costa  and  Kalteyer,3  in  50 
cases,  found  an  average  leucocytosis  of  about  5000  per  c.mm. 
Results  similar  to  the  above  also  have  been  obtained  by  Ewing4 
and  by  Ames,5  in  the   experimental  etherization  of  animals. 

Ether  also  causes  moderate  polycythemia,  but  this  is  due  in 
part  to  inspissation  of  the  blood  by  the  preparatory  treatment  of 

1  "Ueber  die  Einwirkung  der  Aethernarkose  auf  Blut  u.  Urin,"  Inaug.  Dis- 
sert., Berlin,  1896. 

2  Phila.  Med.  Jour.,  1899,  vol.  iii,  p.  390. 

3  Annals  of  Surg.,  1901,  vol.  xxxiv,  p.  329. 

4  N.  Y.  Med.  Jour.,  1895,  vol.  lxi,  p.  257. 

5  Jour.  Amer.  Med.  Assoc.,  1897,  vol.  xxix,  p.  472. 


PATHOLOGICAL  LKUCOCYTOSTS. 


249 


the  patient.  A  slight  diminution  in  hemoglobin  is  commonly, 
but  not  invariably,  found. 

The  effects  of  chloroform  are  similar  to  those  of  ether,  but 
are  more  marked  and  persist  longer.  Solimei1  found  that  the 
leucocytosis  induced  by  chloroform  narcosis,  while  sometimes  dis- 
appearing within  a  few  hours,  often  continues  for  several  days, 
the  duration  of  the  increase  being  related  to  the  amount  of  the 
anesthetic  used  and  to  the  rate  of  its  elimination  from  the  system. 
This  observer  also  detected  a  loss  of  hemoglobin  and  erythrocytes 
with  moderate  poikilocytosis,  and,  after  protracted  narcosis,  de- 
layed coagulability,  the  presence  of  a  methemoglobin  spectrum, 
and  an  increase  in  the  carbon  dioxid  of  the  blood,  with  a  corre- 
sponding diminution  of  oxygen.  Holman2  warns  the  operator 
against  the  danger  from  hemolysis  by  chloroform  in  patients 
whose  hemoglobin  percentages  are  low. 

The  leucocytosis  associated  with  acute  delirium  and  with  con- 
vulsive seizures,  due  to  a  variety  of  causes,  has  been  studied  in 
detail  by  Capps3  and  by  Burrows.4  Under  such  circumstances  the 
increase  is  usually  marked,  and  the  height  of  the  count  in  a  gen- 
eral way  is  dependent  upon  the  severity  of  the  attack.  The 
polynuclear  neutrophiles  are  chiefly  concerned  in  the  increase, 
with  a  consequent  decline  in  the  proportion  of  mononuclear 
forms.  The  leucocytosis  of  this  class  of  diseases  is  discussed 
more  fully  in  Section  VII. 

5.  Experimental  Leucocytosis. — Leucocytoses  not  differing  es- 
sentially from  those  associated  with  various  local  and  general 
infections  may  be  caused  by  the  administration  of  many  drugs, 
chemicals,  organic  principles,  bacteria,  bacterial  proteins,  and  by 
the  application  of  intense  irritants  and  revulsives  to  the  surface 
of  the  body.  No  doubt  many  of  these  leucocytoses  should  be 
classed  either  as  inflammatory  or  as  toxic,  owing  to  the  character 
of  their  exciting  causes,  but  for  the  sake  of  convenience  they  may 
be  grouped  under  this  heading. 

Leucocytoses  resulting  from  the  administration,  subcutaneously 
and  by  the  mouth,  of  various  drugs  and  other  substances  have 
been  studied  chiefly  by  the  Continental  investigators,  to  whom  we 
are  indebted  for  most  of  our  present  knowledge  of  this  subject. 
The  manner  in  which  such  agencies  act  in  causing  the  increase  is 
not  at  all  clear  in  many  instances,  but,  as  a  rule,  the  change  is 
thought  to  be  dependent  upon  chemotactic^  influences,  as  in  in- 

1  Gaz.  degli  Ospedali  e.  d.  Clin.,  1902,  vol.  xxiii,  p.  108. 

2  St.  Paul  Med.  Jour.,  1902,  vol.  iv,  p.  618. 

3  Amer.  Jour.  Med.  Sci.,  1896,  vol.  cxl,  p.  650. 

4  Ibid.,  1899,  vol.  cxvii,  p.  503. 


25° 


THE  LEUCOCYTES. 


flammatory  and  infectious  leucocytoses,  as  well  as  upon  concen- 
tration of  the  blood  from  vasomotor  changes. 

Lowit1  determined  that  a  preliminary  leucopenia  succeeded  by 
a  more  or  less  decided  leucocytosis  followed  the  subcutaneous  in- 
jection of  the  following  substances:  hemialbumose,  pepsin,  nuclein, 
nucleic  acid,  curare,  leech  extract,  tuberculin,  filtered  yeast  cultures, 
pyocyanin,  sodium  urate,  and  uric  acid.  This  change  was  not  ob- 
served, however,  after  the  injection  of  urea. 

Goldscheider  and  Jacob,2  conducting  a  large  number  of  experi- 
ments with  various  organic  animal  extracts,  obtained  results  simi- 
lar to  Lowit's  from  the  injection  of  the  extracts  of  spleen,  thymus, 
and  bone  marrow,  but  found  negative  results  from  the  use  of  the 
extracts  of  thyroid,  pancreas,  and  liver. 

Winternitz 3  studied  the  effects  resulting  from  the  subcutaneous 
injection  of  substances  causing  both  transient  inflammatory  edema 
and  aseptic  abscess  formation  at  the  site  of  the  injection.  In  the 
former  class,  which  includes  neutral  salts  and  dilute  acids  and 
alkalis,  an  increase  in  the  number  of  leucocytes,  amounting  to 
from  40  to  75  per  cent,  of  the  original  count,  was  noted;  and  it 
was  furthermore  found  that  even  although  a  local  necrosis  was 
produced  by  the  injection  of  an  irritating  salt,  the  increase  still 
did  not  become  excessive.  In  the  second  class  of  more  active 
irritants  which  produced  local  abscesses — turpentine,  oil  of 
mustard,  carbolic  acid,  croton  oil,  sapotoxin,  digitoxin,  silver 
nitrate,  cupric  sulphate,  and  salts  0}  mercury  and  of  antimony — the 
leucocytosis  was  much  more  decided  and  of  less  transient  dura- 
tion. As  a  rule,  in  these  experiments  the  height  of  the  leucocy- 
tosis ran  parallel  to  the  intensity  of  the  local  irritation  provoked. 

Pohl4  noted  a  moderate  leucocytosis  following  both  the  inges- 
tion and  the  injection  of  absinthe,  acetic  ether,  extract  of  gentian, 
peppermint,  piper  in,  the  oils  of  anise  and  fennel,  egg  albumin, 
and  sodium  albuminate.  With  the  last  two  substances  he  deter- 
mined that  the  increase  was  greater  when  they  were  given  by  the 
mouth  than  when  administered  subcutaneously ;  the  gain  usually 
ranged  from  about  5  to  50  per  cent,  of  the  normal  count.  This 
investigator  also  found  that  quinin,  caffein,  calomel,  sodium  bicar- 
bonate, ethyl  alcohol,  and  hydrochloric  acid  did  not  cause  a  leucocy- 
tosis, while  bismuth  subnitrate  and  oxid  of  iron  produced  irregular 
results.  Many  of  the  above  experiments  have  been  substantiated 
by  the  later  work  of  von  Limbeck.5  Memmi6  produced  a  moderate 

1  Loc.  cit.  2  Loc.  cit. 

3  Arch.  f.  exp.  Pathol,  u.  Pharmak.,  1895,  vol.  xxxv,  p.  77. 

4  Ibid.,  1889,  vol.  xxv,  p.  51.  • 

5  Loc.  cit.  6  Gaz.  degli  Ospedali  e.  d.  Clin.,  1903,  vol.  xxiv,  p.  995. 


PATHOLOGICAL  LKUOOOYTOSIS. 


persistent  leucocytosis  by  the  daily  intravenous  injection  of  mer- 
curic bichloride  in  ordinary  doses,  the  increase  first  becoming  ap- 
parent a  few  days  after  beginning  the  treatment  and  continuing  as 
long  as  the  drug  was  given.  A  single  injection  generally  caused 
no  increase  unless  the  dose  was  excessive.  In  such  an  instance  the 
maximum  increase  occurred  within  six  hours,  and  the  normal  count 
of  cells  was  reached  within  twenty-four  hours  after  the  injection. 
The  intravenous  injection  of  lecithin  was  found  by  Stassano1  to 
increase  the  number  of  leucocytes,  especially  those  of  the  mononu- 
clear variety,  the  leucocytosis  thus  produced  lasting  four  or  five 
days. 

Wilkinson2  observed  leucocytosis,  preceded  by  leucopenia, 
after  the  injection  of  potassium  io did,  camphor,  quinin,  antipyrin, 
salicin,  salicylic  acid,  nuclein,  and  pilocarpin;  by  the  repeated 
administration  of  the  latter  drug  it  was  found  that  the  granules 
of  the  polynuclear  neutrophiles  disappeared,  although  no  effect 
was  produced  upon  the  granules  of  the  eosinophile  cells.  Von 
Jaksch3  also  studied  the  effects  of  the  injection  of  pilocarpin,  and 
of  the  administration  by  the  mouth  of  nuclein,  and  found  that 
by  either  procedure  a  temporary  and  sometimes  very  marked 
leucocytosis  resulted.  Borini4  found  a  similar  effect  was  pro- 
duced by  aleuron,  but  that  with  digitalis  a  more  prolonged  leuco- 
cytosis occurred.  The  leucocytosis  caused  by  the  ingestion  of 
salicylic  acid,  according  to  Schreiber  and  Zandy,5  gradually  dis- 
appears after  the  drug  has  been  given  for  a  few  days. 

The  effects  of  the  ingestion  of  the  essential  oils  of  peppermint, 
turpentine,  and  cinnamon  have  been  studied  by  Meyer,6  while 
Hirt7  has  investigated  the  influences  of  the  simple  bitters  and 
drugs,  such  as  the  tincture  of  myrrh.  Such  drugs  were  found  to 
cause  a  moderate  but  easily  recognized  leucocytosis.  Krus- 
man,8  by  the  injection  of  spermin  and  of  protalbumose,  and  Bes- 
redka,9  by  a  similar  use  of  carmin  and  of  arsenic  trisulphate,  have 
obtained  varying  degrees  of  increase  in  the  number  of  leucocytes. 
A  marked  increase  is  produced,  according  to  Bohland,10  by  the 
injection  of  morphin,  Dover's  powder,  sodium  salicylate,  pilocar- 
pin, antipyrin,  phenacetin,  and  antijebrin. 

Shaw11  finds  that  a  marked  polynuclear  neutrophile  leucocytosis 

I  Med.  mod.,  1902,  vol.  xiii,  p.  63.         2  Brit.  Med.  Jour.,  1896,  vol.  ii,  p.  836. 

3  Centralbl.  f.  inn.  Med.,  1892,  vol.  xiii,  p.  81. 

4  Centralbl.  f.  Bakt.  u.  Parasit,  1902,  vol.  xxxii,  p.  207. 

5  Deutsch.  Arch.  f.  klin.  Med.,  1899,  vol.  lxii,  p.  242. 

6  Cited  by  von  Limbeck,  loc.  cit. 

7  Ibid.  8  These  de  St.  PetersboUrg,  1898. 
9  Annal.  de  lTnstitut  Pasteur,  1899,  vol.  xiii,  p.  49. 

10  Centralbl.  f.  inn.  Med.,  1899,  vol.  xx,  p.  361. 

II  Jour.  Path,  and  Bacteriol.,  1902,  vol.  viii,  p.  70. 


252 


THE  LEUCOCYTES. 


develops  after  the  administration  of  sodium  cinnamate.  The 
favorable  action  of  this  drug  in  tuberculosis  is  attributed  partly  to 
its  ability  to  excite  and  to  maintain  leucocytosis. 

In  addition  to  the  substances  already  mentioned,  the  leucocy- 
tosis-producing  effect  of  various  purgative  drugs,1  of  the  transfusion 
of  blood  and  of  normal  salt  solution,2  of  the  subcutaneous  use  of 
fibrin  jerment,s  of  hemoglobin,4"  and  of  bacterial  cultures,5  bacterial 
extracts, 6  and  protein7  has  also  been  demonstrated. 

Thymectomy  in  animals  is  followed  by  a  well-marked  leuco- 
cytosis, associated  with  an  increase  in  the  bactericidal  properties 
of  the  blood.  In  a  number  of  experiments  upon  dogs  Cazin8 
determined  that  after  contusions  of  the  abdomen  the  number  of 
leucocytes  was  tripled  or  even  quadrupled  within  three  or  four  hours 
after  the  injury;  the  height  of  the  count  and  the  rapidity  of  the 
onset  of  the  leucocytosis  corresponded  in  these  experiments  to  the 
severity  of  the  visceral  injuries  inflicted.  The  same  author  found 
but  a  trifling  leucocytosis  after  bullet  wounds  of  the  abdomen  with 
intestinal  perforation. 

IV.  LYMPHOCYTOSIS. 

An  increase,  whether  relative  or  absolute,  in  the  lymphocytes 
above  the  number  normal  in  health  is  known  as  lymphocytosis. 
The  word  mononucleosis  also  is  used  to  denote  this  change.  Rela- 
tive lymphocytosis  involves  simply  a  gain  in  the  percentage  of 
lymphocytes  without  a  coincident  increase  in  the  total  leucocyte 
count.  Absolute  lymphocytosis,  on  the  other  hand,  is  character- 
ized by  an  increase  above  normal  both  in  the  percentage  of  lympho- 
cytes and  in  the  total  number  of  leucocytes.  Barring  lymphatic 
leukemia,  in  which  the  lymphocytes  are  both  relatively  and  abso- 
lutely in  excess,  lymphocytosis  is  almost  always  a  relative  condi- 
tion, or  at  least  it  is  not  accompanied  by  a  decided  rise  in  the 
total  leucocyte  count. 

The  increase  in  the  proportion  of  lymphocytes  is  moderate  in 
most  instances,  the  greater  number  of  differential  counts  showing 
percentages  of  these  cells  ranging  from  50  to  70,  in  comparison 
with  the  maximum  normal  percentage,  about  30.  These  figures, 
of  course,  refer  to  the  blood  of  adults,  for  in  children  the  increase 

1  De  Rienzi  and  Boeni,  Gaz.  degli  Ospedali  e.  d.  Clin.,  1898,  vol.  xix,  p.  1570. 

2  Hand,  N.  Y.  Med.  Jour.,  1900,  vol.  lxxi,  p.  556. 

3  Birk,  "Das  Fibrin-Ferment  im  lebenden  Organismus,"  Dorpat,  1880. 

4  Bojanus,  "Exp.  Beitrage  z.  Physiol,  u.  Pathol,  d.  Blutes,"  Dorpat,  1881. 

5  Hankin  and  Kanthack,  Centralbl.  f.  Bakt.  u.  Parasit,  1892,  vol.  xvii,  p.  782. 
8  Buchner,  Arch.  f.  Hyg.,  1890,  vol.  x,  p.  84.  7  Ibid. 

8  Sem.  med.,  1903,  vol.  xxiii,  p.  351. 


LYMPHOCYTOSIS. 


253 


is  generally  greater,  owing  to  the  higher  proportion  of  lympho- 
cytes normally  found  at  this  period  of  life.  A  differential  count, 
which  shows,  for  instance,  60  per  cent,  of  lymphocytes,  means  a 
decided  lymphocytosis  in  the  adult,  but  is  entirely  within  the 
normal  limits  in  the  young  infant.  Either  type  of  cells,  large  or 
small,  may  predominate,  or  the  change  may  not  involve  any  con- 
spicuous deviation  from  the  normal  ratio  of  one  form  to  the  other. 
Frequently  it  happens  that  the  two  varieties  possess  such  similar 
characteristics  that  it  is  impossible  to  determine  which  prevails. 
Occasionally  the  lymphocytosis  depends  largely  upon  unusually 
large  percentages  of  the  so-called  " transitional"  forms,  while  in 
other  instances,  notably  in  the  lymphocytosis  of  von  Jaksch's 
anemia,  rickets,  syphilis,  variola,  and  scarlatina,  the  increase 
chiefly  involves  Ehrlich's  large  mononuclear  forms,  reputed  to 
originate  in  the  marrow. 

Lymphocytosis  may  be  due  either  to  changes  in  the  distribu- 
tion of  the  cells  through  the  circulatory  system,  or  to  their  in- 
creased production  and  output  by  the  lymphatic  tissues.  Ehr- 
lich1  attributes  lymphocytosis  to  the  local  irritation  of  certain 
areas  of  lymphatic  glands  which  produces  an  increased  circulatory 
activity  in  these  situations,  in  consequence  of  which  large  numbers 
of  lymph  elements  are  swept  mechanically  from  the  lymphatics 
and  enter  the  general  circulation.  He  does  not  regard  the  change 
as  an  expression  of  an  active  chemotactic  reaction,  to  which  the 
lymphocytes  are  insensible.  It  also  appears  reasonable  to  pre- 
sume that  the  lymphocytosis  which  often  accompanies  leucopenia 
may  be  traced  to  still  another  factor,  that  of  negative  chemotaxis,. 
which  diminishes  the  number  of  polynuclear  neutrophiles  and 
thus  brings  about  a  relative  increase  in  the  lymphatic  elements, 
upon  which  the  repellent  action  is  not  exerted. 

Lymphocytosis  has  been  observed  in  a  number  of  pathological 
conditions,  but  its  presence  may  be  considered  physiological  in 
but  a  single  instance — in  the  blood  0]  infants  and  young  children,, 
in  whom  such  a  change  is  entirely  normal.  During  the  decline 
of  life,  on  the  other  hand,  the  lymphocytes  are  relatively  dimin- 
ished. This  tendency  toward  a  lymphocytic  increase  in  infantile 
life,  which  becomes  less  notable  as  the  child  matures,  is  prone  to 
become  markedly  exaggerated  in  many  of  the  forms  of  secondary 
anemia  from  which  children  suffer,  especially  the  anemias  second- 
ary to  syphilis,  tuberculosis,  rachitis,  gastro-enteritis,  and  scurvy; 
less  commonly,  it  has  been  observed  in  the  acute  infections. 

Lactation,  conditions  of  cachexia,  and  great  debility  in  the" 
adult  are  in  many  instances  accompanied  by  abnormally  high  per- 

1  Loc.  cit. 


254 


THE  LEUCOCYTES. 


centagcs  of  lymphocytes  in  the  blood.  It  is  a  well-known  fact 
that  differential  counts  show  a  higher  percentage  of  mononuclear 
non-granular  elements  in  the  blood  of  the  enfeebled  and  poorly 
nourished  than  in  that  of  the  active  and  vigorous  individual. 

Similar  changes  are  frequently  associated  with  the  terminal 
stages  of  a  number  of  diseases,  and  may  be  found  after  hemorrhage 
from  various  causes — trauma,  hemophilia,  purpura,  and  following 
splenectomy. 

Lymphocytosis,  sometimes  decidedly  marked,  is  common  in 
certain  of  the  severe  anemias,  especially  in  chlorosis,  pernicious 
anemia,  Addison's  disease,  and  in  syphilitic  and  tuberculous 
secondary  anemias;  it  may  be  observed  in  certain  of  the  infections, 
such  as  enteric  fever,  malarial  fever,  Malta  fever,  scarlet  fever, 
measles,  diphtheria,  pertussis,  variola,  phthisis,  pneumonia, 
plague,  and  trypanosomiasis.  A  high  degree  of  lymphocytosis 
has  been  reported  by  Labbe  and  Bernard1  in  tropical  hemato- 
chyluria  resulting  from  filariasis.  Roger's  contention,2  that  in- 
fections characterized  by  lymphocytosis  are  of  protozoan  type, 
is  scarcely  tenable,  in  view  of  the  occurrence  of  this  change  in 
enteric  fever,  in  Malta  fever,  and  in  tuberculosis,  to  name  but 
three  bacterial  infections  in  which  the  lymphocytes  are  increased. 

Diseases  involving  the  spleen  and  lymphatic  glands  are  often  the 
cause  of  a  varying  degree  of  increase  in  the  lymphocytes,  common 
examples  of  such  conditions  being  chronic  malarial  splenic  tumors ; 
kala-azar;  simple,  syphilitic,  and  tuberculous  adenitis;  and  ma- 
lignant neoplasms,  especially  sarcoma,  of  the  lymph  glands.  On 
the  contrary,  extreme  decrease  in  the  lymphocytes  develops  in 
consequence  of  obliteration  of  the  lymph  channels  by  malignant 
tumors.  Enlargement  of  the  thyroid  gland  relatively  increases  the 
lymphocytes,  as  does  that  systemic  taint  known  as  the  constitutio 
lymphatica.    Chloroma  may  provoke  high  absolute  lymphocytosis. 

Distinct  lymphocytosis  has  been  observed  by  Wilkinson3  after 
the  injection  of  quinin  hydro  chlorate;  and  by  Perry4  and  Lepine5 
as  the  result  of  the  administration  of  thyroid  extract.  It  also  follows 
the  injection  of  tuberculin,  pilocarpin,  and  emulsion  of  cancerous 
tissue. 

From  a  clinical  viewpoint  lymphocytosis  is  of  value  chiefly  in 
the  diagnosis  of  lymphatic  leukemia.  Marked  absolute  increase 
in  the  number  of  lymphocytes,  associated  with  enlargement  of  the 
lymphatic  glands,  forms  a  pathognomonic  picture  of  this  disease. 

1  Sem.  med.,  1902,  vol.  xxii,  p.  433. 

2  "Infectious  Diseases,"  Eng.  trans,  by  Gabriel,  New  York  and  Philadelphia, 
1903. 

3  Loc.  cit.  4  Med.  Record,  1896,  vol.  1,  p.  289. 
5  Sem.  med.,  1902,  vol.  xxii,  p.  409. 


EOSINOPHILS. 


255 


The  recognition  of  a  doubtful  case  of  syphilis  may  be  facilitated 
by  the  occurrence  of  lymphocytosis  plus  eosinophilia. 

V.  EOSINOPHILIA. 

The  term  eosinophilia  is  used  to  denote  an  increase  above  the 
normal  standard  in  the  number  of  eosinophiles  in  the  circulating 
blood,  this  change  usually,  but  not  necessarily,  being  associated 
with  a  coincident  increase  in  the  relative  percentage  of  these  cells 
to  the  other  forms  of  leucocytes.  Thus  interpreted,  eosinophilia 
is  a  condition  of  absolute  increase,  in  contradistinction  to  a  purely 
relative,  gaimin  percentage,  to  which  the  term  is  not  strictly  appli- 
cable. 

For  the  sake  of  uniformity  it  is  customary  to  speak  of  the  per- 
centage of  eosinophiles  rather  than  of  their  actual  number,  but 
in  order  to  determine  accurately  the  presence  or  absence  of  eosino- 
philia it  is  also  essential  in  every  instance  to  calculate  the  number 
of  eosinophiles  to  the  c.mm.  of  blood  from  data  obtained  by  a 
numerical  estimate  and  a  differential  count  of  the  leucocytes, 
thus: 

Total  number  oj  leu-         Percentage  0}  eosinophiles  to   _    Total  number  of  eosin- 
cocytes  per  c.mm.  other  forms  of  leucocytes.      ~       ophiles  per  c.mm. 

The  necessity  for  such  a  calculation  is  forcibly  illustrated  in 
myelogenous  leukemia,  since  in  this  condition  the  relative  per- 
centage of  eosinophiles  is  often  well  within  the  normal  limits, 
and  yet  a  striking  degree  of  eosinophilia  may  exist.  For  example, 
in  a  given  case  of  this  form  of  leukemia,  the  blood  count  shows 
300,000  leucocytes  per  c.mm.  with  5  per  cent,  of  eosinophiles. 
This  percentage,  interpreted  into  the  actual  number  of  cells, 
means  an  eosinophilia  of  15,000  per  c.mm.,  or  an  increase  of 
thirty-fold  in  excess  of  the  highest  normal  figure. 

On  the  basis  of  a  variation  in  the  normal  number  of  leucocytes 
of.  from  5000  to  10,000  per  c.mm.,  the  absolute  number  of  eosino- 
philes may  range  from  25  to  500  per  c.mm.  in  the  blood  of  the 
healthy  adult.  An  increase  in  excess  of  this  maximum  standard, 
regardless  of  the  percentage  indicated  by  the  differential  count,  con- 
stitutes eosinophilia. 

Granting  the  accuracy  of  the  current  view  that  the  hemic 
eosinophiles  are  purely  myelogenous  elements,  their  increase  in 
the  blood  may  be  attributed  to  the  influence  of  chemotaxis,  prob- 
ably of  a  specific  and  selective  character.  Under  the  influence  of 
such  a  stimulus  the  eosinophiles  are  attracted  from,  and  perhaps 
overproduced  by,  the  bone  marrow,  and  are  thrown  into  the  gen- 


2^6  THE  LEUCOCYTES. 

oral  circulation  in  large  numbers.  It  is  also  possible  that  to  a 
slight  extent  their  proliferation  from  like  cells  may  occur  m  the 
blood  stream  as  well.  . 

Increase  in  the  number  of  eosinophils  occurs  as  a  physiolog- 
ical change  in  young  injants,  in  women  during  the  menstrual  period, 
and  after  coitus.  With  these  three  exceptions  the  presence  of 
eosinophilia  is  always  to  be  regarded  as  an  evidence  of  some 
pathological  condition.  .    .  . 

Once  believed  to  be  a  pathognomonic  sign  of  leukemia,  m  tne 
light  of  more  recent  investigations  eosinophilia  is  now  known  to 
be  associated  with  diseases  of  almost  every  conceivable  nature; 
in  fact,  it  has  been  reported  in  so  large  a  number  of  conditions 
of  such  widely  dissimilar  pathogenesis  that  its  value  as  a  clinical 
sio-n  must  be  largely  restricted.  Inasmuch  as  many  of  these  re- 
ported instances  of  eosinophile  increase  lack  verification,  it  can 
only  prove  confusing  to  give  here  a  list  of  the  many  pathological 
states  in  which  the  change  is  reputed  to  have  been  observed. 
The  following  list,  based  upon  the  work  of  Cannon,  Zappert 
Gollasch,3  T.  R.  Brown,4  von  Noorden,5  and  others,  includes  only 
those  diseases  in  which  eosinophilia  is  observed  with  a  great  de- 
gree of  constancy.    Such  conditions  are: 

I.  Diseases  of  the  Skin. 

Dermatitis  herpetiformis.  Pellagra. 

Eczema.  Pemphigus. 

Erythema  multiforme.  Prurigo. 

Herpes  zoster.  Psoriasis. 

Leprosy.  Scleroderma. 

Lupus.  Urticaria. 

II.  Helminthiasis. 

SS" iSSiS-  Soit  intestines  infection. 


Bilharziasis. 


Teniasis. 


Filariasis.  '  Trichiniasis. 
Hydatid  disease. 


III.  Diseases  o)  the  Bones. 


Multiple  periostit 


Hypertrophy.  muiupie  yen 

Malignant  neoplasms.  Osteomalacia. 

1  Deutsch.  med.  Wochenschr.,  1892,  vol.  xviii,  p.  206. 

»  Zehschr.  f.  klin.  Med.,  1893,  vol.  xxiii,  p.  227;  also  Wien.  klin,  Wochenschr. 

,2,  vol.  v,  p.  347-  .     ..  , 

3  Fortschr.  d.  Med.,  1889,  vol.  vu,  p.  301-... 

4  Johns  Hopkins  Hosp.  Bull.,  1897,  vol.  vm,  p.  79- 

5  Zeitschr.  f.  klin.  Med.,  1892,  vol.  xx,  p.  98. 


EOSINOPHILS 


257 


IV.  Post-febrile. 

Malarial  fever.  Scarlet  fever. 

Pneumonia.  Septicemia. 
Rheumatic  fever.  Varicella. 

V.  Bronchial  Asthma. 


VI.  Myelogenous  Leukemia. 


In  addition  to  the  conditions  listed  above,  eosinophilia  also 
occurs,  but  with  less  constancy,  in  some  forms  of  the  high-grade 
secondary  anemia  of  childhood,  purpura,  hemorrhagic  effusions, 
gonorrhea,  syphilis,  malignant  disease,  and  in  fibrinous  bron- 
chitis. It  is  also  seen  in  many  cases  of  splenomegaly  and  after 
splenectomy,  its  development  under  the  latter  circumstance 
being  regarded  as  a  compensatory  condition.  An  increase  in 
the  percentage  of  eosinophiles  has  also  been  noted  in  conditions  of 
starvation.  In  scarlet  fever  the  eosinophiles  usually  persist,  in 
spite  of  the  coexisting  polynuclear  leucocytosis,  and  the  same 
peculiarity  may  often  be  found  in  trichiniasis,  fllariasis,  hydatid 
disease,  and  infection  with  intestinal  parasites. 

Eosinophilia  may  be  produced  experimentally  by  the  injection 
of  a  number  of  medicaments,  such  as  antipyrin,  camphor,  nu- 
clein,  phosphorus,  pilocarpin,  tuberculin,  and  many  of  the'  iron 
salts.  T.  R.  Brown1  found  high  eosinophilia  (12  per  cent,  in  a 
leucocyte  count  of  30,000)  in  acetanilid  poisoning.  The  writer 
detected  eosinophilia  in  3  cases  of  poisoning  by  nitrites. 

Neusser  2and  his  school  have  contended  that  eosinophilia  is 
symptomatic  of  an  extensive  group  of  diseases,  chiefly  those  in- 
volving the  sympathetic  nervous  system,  the  sexual  organs,  and  a 
long  list  of  disorders  which  they  attributed  to  the  uxanthin  dia- 
theses.^ Most  of  these  views  have  been  unsubstantiated,  many 
are  misleading,  and  a  few  can  be  shown  to  be  fanciful.  Those 
who  are  inclined  to  investigate  some  of  the  remarkable  claims 
made  by  Neusser  as  to  the  diagnostic  and  prognostic  value  of 
eosinophilia  are  referred  to  his  original  communication  on  the 
subject. 

>  Diminution  in  the  number  of  eosinophiles  occurs  as  a  physiolog- 
ical process  during  digestion  and  after  active  muscular  exercise. 
It  is  observed  usually  in  lymphatic  leukemia,  tuberculosis,  during 
the  febrile  stages  of  diphtheria,  influenza,  pneumonia,  enteric  fever, 
and  septicemia,  frequently  after  hemorrhage,  and  in  the  terminal 

1  Md.  Med.  Jour.,  1902,  vol.  xlv,  p.  307. 
Wien.  klin.  Wochenschr.,  1894,  vol.  vii,  p.  737. 


2^8  THE  LEUCOCYTES. 

states  of  many  diseases.  The  number  of  eosinophiles  is  said  to  be 
diminished  after  castration.  The  writer  has  found  a  decrease  or 
even  absence  of  eosinophiles  in  the  majority  of  cases  of  chlorosis 
and  pernicious  anemia. 

The  chief  clinical  value  attached  to  eosinophils  relates  to  its 
presence  in  trichiniasis,  in  filariasis,  in  intestinal  helminthiasis, 
and  in  hydatid  disease,  in  which  infections  it  has  been  shown  to 
be  a  sign  of  great  reliability.  It  may,  however,  be  absent  m  the 
later  stages  of  these  infections.  . 

In  the  diagnosis  of  an  exanthema  which  is  suggestive  either  ot 
scarlet  fever  or  of  measles,  eosinophilia  points  to  the  former  dis- 
ease, for  it  does  not  occur  in  the  latter. 

The  association  of  eosinophilia  and  lymphocytosis  constitutes  a 
blood  change  which  may  be  helpful  in  the  recognition  of  an  ob- 
scure case  of  syphilis.  [  '  :< 

High  percentages  of  eosinophiles  in  chlorosis,  m  pernicious 
anemia,  and  after  hemorrhage  are  generally  regarded  as  an  evi- 
dence of  good  regenerative  powers  of  the  hemogemc  organs,  and 
are  therefore  of  favorable  import  (Rieder).1 


VI.  BASOPHILIA. 

Increase  in  the  number  of  basophiles  in  the  circulating  blood 
is  of  rare  occurrence,  having  been  observed  in  but  few  diseases 
except  the  myelogenous  variety  of  leukemia,  m  which  this  change 
is  quite  constant,  and  sometimes  most  striking;  the  basophiles  in 
this  disease  may  constitute  10,  20,  or  even  30  per  cent,  ol  all 
forms  of  leucocytes.  The  increase  may  involve  the  hnely 
granular  or  the  coarsely  granular  (mast  cell)  forms  or  both 

Until  recently  but  little  attention  has  been  paid  by  hematolo- 
gists  to  the  general  circulatory  form  of  basophilia,  although  the 
local  increase  of  the  basophiles  under  various  conditions  has  been 
well  investigated.  Canon2  has  reported  an  increase  of  the  mast 
cells  in  a  case  of  chlorosis  and  in  various  skin  diseases.  Sherring- 
ton3 has  observed  a  similar  blood  change  in  patients  dying  m  the 
reaction  stage  of  Asiatic  cholera.  A.  E.  Taylor4  states  that  he  has 
seen  a  notable  circulatory  basophilia  in  a  case  of  carcinoma,  with 
marked  cachexia,  but  without  bone  metastases;  m  a  case  ot 
gonorrhea:  in  a  case  of  mycosis  fungoides;  and  m  two  cases  ot 
septic  bone  disease.    Basophilia  has  also  been  observed  m  variola, 

1  Loc.  cit.  '         2  Deutsch.  med.  Wochenschr.,  1892,  vol.  xviii,  p.  206. 

3  Proc.  Roy.  Soc,  London,  1894,  vol.  lv,  p.  189.  Marine  " 

*  -  Contributions  from  the  William  Pepper  Laboratory  of  Clinical  Medicine, 

Philadelphia,  1900,  p.  148. 


MYELEMIA. 


259 


splenic  anemia,  Hanoi's  cirrhosis,  and  in  hydatid  disease  and  other 
forms  of  helminthiasis.  The  writer  found  a  mast  cell  basophilia 
of  2  per  cent.,  with  a  leucocytosis  of  13,000,  in  a  case  of  plumbism, 
and  has  noted  large  numbers  of  mast  cells  in  suppurative  appen- 
dicitis, pernicious  anemia,  filariasis,  and  trichiniasis. 

Owing  to  our  imperfect  understanding  of  this  condition  no 
theory  regarding  the  production  of  basophilia  is  as  yet  generally 
acceptable.  It  is  possibly  due  to  the  influence  of  a  specific  chemo- 
tactic  substance,  in  response  to  which  the  basophiles  are  attracted 
from  the  bone  marrow  and  enter  the  general  circulation. 


VII.  MYELEMIA. 

The  presence  in  the  circulating  blood  of  myelocytes,  in  small 
or  m  large  numbers,  is  known  as  myelemia.  As  previously  re- 
marked, this  condition  is  invariably  to  be  regarded  as  patholog- 
ical, since  myelocytes  are  never  found  in  the  blood  of  the  normal 
individual. 

The  most  striking  example  of  myelemia  is  to  be  found  in 
the  myelogenous  form  of  leukemia,  in  which  condition  this 
change  constitutes  one  of  the  most  conspicuous  features  of  the 
blood  picture.  Myelocytes  occur  in  the  blood  in  this  disease  in 
greater  absolute  and  relative  numbers  and  with  greater  constancy 
than  m  any  other  condition— a  fact  which  is  of  the  greatest  diag- 
nostic value.  The  degree  of  increase  may  be  enormous,  as  illus- 
trated by  a  case  of  the  author's,  in  which  the  actual  number  of 
myelocytes  was  found  to  be  192,738  per  c.mm.,  or  27.3  per  cent 
of  all  forms  of  cells  in  a  total  leucocyte  count  of  706,000.  In 
instances  of  splenomegaly  with  anemia  and  moderate  leucocytosis 
small  numbers  of  myelocytes  have  been  reported  as  a  constant 
finding  by  Emile  Weil  and  Clerc.1  Kurpjuweit,2  in  malignant  dis- 
ease with  bone  metastases,  found  as  high  as  17  per  cent,  of  mye- 
locytes, and  he  regards  this  myelemia  as  a  sign  of  gravely  altered 
hemogenesis.  (See  "  Malignant  Disease.")  Von  Jaksch3  noted 
marked  myelemia  m  his  symptom-complex,  termed  multiple  peri- 
ostitis with  myelocythemia. 

Less  frequently  myelocytes  are  observed  in  lymphatic  leu- 
kemia and  m  Hodgkirfs  disease,  but  in  these  conditions  their 
occurrence  is  inconstant  and  their  increase  trivial.  Small  nu 
bers  of  myelocytes  (from  0.5  to  2  or  3  per  cent.)  are  found 


num- 
in 


Arch.  gen.  de  Med.,  1902,  vol.  cxc,  p.  560. 

Deutsch.  Arch.  f.  klin.  Med.,  1903,  vol.  Ixxvii  p  cc, 

Zeitschr.  f.  Heilk.,  1901,  vol.  xxii,  p.  259. 


260 


THE  LEUCOCYTES. 


almost  every  case  of  primary  pernicious  anemia,  and  are  not  un- 
common in  marked  cases  of  chlorosis  and  in  many  of  the  severe 
forms  of  secondary  anemia  due  to  various  causes.  They  are  fre- 
quently met  with  in  such  conditions  as  pneumonia,  septicemia, 
diphtheria,  syphilis,  malignant  disease,  rachitis,  tuberculosis  osteo- 
myelitis, osteomalacia,  Addison's  disease,  and  the  malarial  jevers. 
The  writer  has  found  them  also  in  the  following  conditions:  car- 
bon monoxid  poisoning,  hepatic  cirrhosis,  acute  gout,  malignant 
endocarditis,  exophthalmic  goiter,  as  well  as  in  the  above-named 
affections.  One  is  forcibly  impressed  with  the  almost  constant 
presence  of  myelocytes  in  the  estivo-autumnal  type  oi  malarial 
jever  in  severe  septic  injections,  and  in  enteric  jever  m  childhood, 
both'in  the  early  stages  of  the  disease  and  during  the  later,  post- 
febrile anemic  period.  Small  numbers  of  myelocytes  have  been 
reported  also  in  many  other  conditions,  chiefly  those  associated 
with  leucocytosis,  with  anemia,  or  with  both. 

Increased  activity  of  the  bone  marrow,  whereby  the  myelocytes 
are  forced  into  the  blood  stream,  is  in  all  probability  responsible 
for  the  production  of  myelemia.  In  response  to  an  increased 
demand  for  leucocytes  the  marrow  becomes  so  overstimulatea 
that  many  immature  forms  of  leucocytes,  or  myelocytes,  acciden- 
tally find  their  way  into  the  general  circulation,  their  passage  from 
the  marrow  no  doubt  being  accomplished  largely  by  emigration. 
It  is  furthermore  now  believed  that  substances  which  are  posi- 
tively chemotactic  for  the  polynuclear  neutrophils  also  exert  a 
similar  attractive  influence  upon  their  immediate  precursors  the 
myelocytes,  stimulating  their  increased  proliferation  m  the  bone 
marrow  and  exciting  their  emigration  from  this  tissue  into  the 
blood  stream. 


VIII.  LEUCOPENIA. 

Decrease  below  the  normal  standard  in  the  number  of  leuco- 
cytes in  the  peripheral  blood  is  known  as  leucopenia  or  hypoleuco- 
cytosis.  Such  a  condition,  like  its  antithesis,  leucocytosis,  may  be 
the  result  of  either  physiological  or  pathological  causes.  Owing 
to  the  variation  in  the  normal  number  of  leucocytes  m  different 
individuals,  it  is  difficult  to  determine  arbitrarily  just  what  degree 
of  decrease  may  be  considered  as  a  leucopenia,  but  it  is  sate  to 
apply  the  term  to  any  leucocyte  count  decidedly  below  5000  cells 
to  the  cm  The  number  of  leucocytes  is  rarely  reduced  to 
less  than  3000,  except  in  certain  of  the  essential  anemias,  m 
which  their  decline  to  one-tenth  the  maximum  normal  figure 
or  even  less  is  occasionally  to  be  observed.    The  most  extreme 


LEUCOPENIA. 


26l 


instance  of  leucopenia  on  record  has  been  reported  by  Koblanck,1 
who  found  but  a  single  leucocyte  in  a  careful  search  through 
twenty  stained  cover-glass  preparations  of  blood  from  a  man  of 
twenty-five  years,  suffering  from  epilepsy;  the  exact  numerical 
estimate  of  the  leucocytes  in  this  case  is  not  given  in  detail. 

The  decrease  may  be  accompanied  by  no  deviation  from  the 
normal  percentages  of  the  different  varieties  of  leucocytes,  or  it 
may  involve  a  more  or  less  decided  gain  in  the  lymphocytes,  the 
latter  being  the  more  common  change  of  the  two. 

According  to  the  nature  of  its  underlying  causes,  leucopenia  may 
be  considered  clinically  as  either  physiological  or  pathological. 


Physiological  Leucopenia. 

The  decrease  in  the  number  of  leucocytes  observed  in  several 
physiological  states  is  generally  attributed  to  vasomotor  influ- 
ences which  produce  changes  in  the  distribution  of  the  leucocytes 
throughout  the  system.  Such  changes  occur  from  the  effect  of 
prolonged  cold,  and  brief  hot,  baths.2  Decastelle3  has  found  that 
a  temporary  leucopenia  may  be  produced  experimentally,  by  stim- 
ulation 0]  sensory  nerves,  this  procedure  causing  a  reflex  con- 
traction of  the  abdominal  vessels  and  a  consequent  retention  of 
large  numbers  of  circulating  leucocytes  in  this  part  of  the  vascu- 
lar system.  The  variations  in  the  number  of  cells  range  from 
20  to  30  per  cent,  of  the  original  count;  the  maximum  decrease 
occurs  usually  within  three  or  four  minutes,  and  in  most  instances 
does  not  persist  longer  than  ten  or  fifteen  minutes.  Reduction 
of  blood  pressure  is  promptly  followed  by  a  very  transient  diminu- 
tion in  the  leucocytes  of  the  peripheral  blood. 

Malnutrition  and  starvation  are  also  potent  factors  in  the  pro- 
duction of  leucopenia,  the  decrease  dependent  upon  such  causes 
frequently  being  most  pronounced.  The  much-cited  case  of  the 
faster,  Succi,  is  a  good  example  of  the  effects  produced  upon  the 
leucocytes  by  abstinence  from  food.  Luciani4  found  in  the  blood 
of  this  individual  a  decrease  in  the  number  of  leucocytes  from 
14,53°  to  861  per  c.mm.  after  a  seven  days'  fast;  on  the  eighth 
day  an  increase  to  1530  occurred,  this  being  the  average  count 
noted  during  the  remaining  twenty-one  days  of  the  fast.  The 
subnormal  leucocyte  counts  which  are  often  met  with  in  many 
of  the  infirm  and  the  greatly  enfeebled  can  be  traced  to  the  effects 
of  faulty  nutrition  and  to  the  malassimilation  of  food. 

3  5?  uS\?.issf }■>  Berlin>  l889-  2  Winternitz,  loc.  cit. 

Wien.  klin.  Wochenschr.,  1899,  vol.  xii,  p.  395. 
Das  Hungern"  (German  translation  by  O.  Frankel),  Hamburg  and  Leipsic, 


262  the  leucocytes. 

Pathological  Leucopenia. 
Leucopenia,  or  at  least  an  absence  of  leucocytosis,  occurs  dur- 
ing the  course  of  a  number  of  general  infectious  diseases,  promi- 
nent among  which  are  the  following:  enteric  jever,  paratyphoid 
jever,  measles,  rotheln,  influenza,  leprosy,  Malta  jever ,  the  malarial 
jevers,  trypanosomiasis,  and  non-septic  tuberculosis.  In  acute 
infections  which  are  ordinarily  accompanied  by  leucocytosis  the 
combined  influences  of  an  intense  infection  and  feeble  resisting 
powers  on  the  part  of  the  individual  may  produce  a  distinct 
leucopenia,  or  may  prevent  the  development  of  the  characteristic 
increase.  This  is  well  illustrated  by  the  low  counts  which  some- 
times are  found  in  severe  cases  of  pneumonia  and  of  appendicitis. 

Leucopenia,  often  pronounced,  is  not  uncommon  in  chlorosis 
and  in  pernicious  'anemia,  being  much  more  frequent  and  more 
decided  in  the  latter  disease.  A  well-marked  leucopenia  may  be 
expected  in  about  one-fourth  of  all  cases  of  chlorosis,  and  m 
quite  three-fourths  of  cases  of  pernicious  anemia.  It  is  also  often 
met  with  in  some  high-grade  secondary  anemias,  notably  in  those 
due  to  syphilis  and  to  rachitis,  and  in  splenic  anemia. 

D'Orlandi1  has  called  attention  to  the  frequency  with  which 
leucopenia  is  observed  in  certain  of  the  severer  forms  of  chronic 
gastro-enteritis  in  young  infants.  In  a  fatal  case  of  primary 
infectious  pharyngitis  reported  by  P.  K.  Brown,2  the  leucocytes 
never  numbered  more  than  400  to  the  c.mm. 

In  the  anemias  accompanied  by  a  decrease  in  the  leucocytes, 
especially  in  primary  pernicious  anemia,  the  rule  holds  good  that 
the  more  intense  the  oligocythemia  and  oligochromemia,  the 
greater  the  degree  of  leucopenia.  Ehrlich3  attributes  the  de- 
crease in  such  cases  to  a  lessened  proliferative  function  of  the 
bone  marrow,  in  consequence  of  which  there  is  a  diminution  m 
the  output  of  leucocytes  by  this  organ. 

In  leukemia  an  acute  intercurrent  infection  may  produce  an 
abrupt  and  marked  fall  in  the  number  of  leucocytes,  as  m  Cabot  s 
remarkable  case  of  lymphatic  leukemia,4  in  which,  as  the  conse- 
quence of  a  fatal  septicemia,  the  leucocytes  fell  in  three  weeks 
from  40,000  to  419  per  c.mm. 

Decrease  in  the  number  of  leucocytes  may  be  caused  experi- 
mentally by  the  administration  of  various  drugs  and  other  sub- 
stances. Bohland5  found  that  it  followed  the  injection  of  ergot 
sulphonal,  tannic  acid,  camphoric  acid,  atropm,  agaricm,  and 

1  Rev.  mensuelle  des  malad.  de  l'Enfance,  1899,  vol.  xvii,  p.  300. 

2  Amer.Med.,  1902,  vol.  iii,  p.  649.  5  ^  cit\ 
4  Loc.  cit. 


LEUCOPENIA. 


263 


picrotoxin.  Delczcne's1  investigations  showed  that  a  marked 
decrease  results  from  the  injection  of  various  anticoagulant  sub- 
stances, such  as  peptone,  diastase,  and  eel  serum;  he  attributes 
the  leucopenia  thus  produced  to  two  factors— actual  destruction 
in  the  circulation  of  some  of  the  leucocytes  and  dilatation  of  the 
blood  vessels,  in  which  the  undestroyed  cells  tend  to  accumulate. 
The  transient  leucopenia  which  precedes  an  increase  in  the 
leucocytes  has  been  discussed  elsewhere.    (See  p.  239.) 

O.  K.  Williamson2  has  shown  that  an  increased  destruction 
of  leucocytes  is  attended  by  an  increased  excretion  of  uric  acid  in 
the  urine.  His  studies  apparently  prove  that  in  cases  in  which 
a  rise  in  the  phosphoric  acid  curve  follows  a  fall  in  the  leucocyte 
curve  and  in  the  number  of  granular  cells  especially,  this  rise 
corresponds  with  a  rise  in  the  uric  acid  curve. 

1  Nouveaux  Montpel.  med.,  1898,  vol.  vii,  pp.  694,  733,  765,  and  789. 

2  Lancet,  1903,  vol.  i,  p.  657. 


SECTION  V. 


DISEASES  OF  THE  BLOOD. 


SECTION  V. 
DISEASES  OF  THE  BLOOD. 


I.  CHLOROSIS. 

Lorrain  Smith/  by  his  carbonic  oxid  method, 
General      estimates  that  the  total  volume  of  blood  is  greatly 
Features,    increased  in  chlorosis,  this  excess  being  due  to  an 
increase  in  the  bulk  of  normal  plasma,  and  being 
more  marked  the  severer  the  case.    Taking  the  normal  blood 
volume  as  3240  c.c,  Smith  found  in  21  chlorotics  an  average  of 
4883  c.c.    Although  the  oxygen  capacity  of  a  blood  unit  is  dimin- 
ished about  one-half,  the  total  oxygen  capacity  of  the  blood  remains 
approximately  normal— 95  per  cent.    Lloyd  Jones 2  also  believes 
in  a  plasma  increase  in  chlorosis,  but  further  confirmation  of  the 
above  experimental  work  is  needed  before  this  presumption  can 
be  registered  as  a  fact. 

The  proportion  of  dry  residue  of  the  whole  blood  is  subnormal, 
approximating  in  the  severe  case  between  one-half  and  one-third 
the  normal  amount,  with  a  corresponding  increase  in  water. 

There  is  a  decided  loss  of  blood  albumin,  mainly  referable  to 
the  oligochromemia,  but,  as  Biernacki 3  has  pointed  out,  also  due, 
at  least  in  severe  cases,  to  a  deficiency  in  the  amount  of  serum 
albumin.  In  high-grade  chlorosis  this  author  found  that  the 
dry  residue  of  the  whole  blood  might  contain  a  normal  iron  con- 
tent, the  inference  being  that  in  such  instances  the  albumin  loss 
was  not  always  confined  to  the  hemoglobin. 

The  blood  drop  is  exceedingly  pale  and 
Appearance  watery-looking,  and  flows  so  abundantly  from  the 
of  the       puncture  that  it  actually  seems  as  if  the  whole 
Fresh  Blood,  mass  of  blood  in  the  body  must  be  increased;  a 
large-sized  drop  usually  follows  the  slightest  prick 
of  the  needle,  in  spite  of  the  obviously  anemic  appearance  of  the 
patient— a  marked  contrast  to  the  difficulty  commonly  experi- 
enced in  pernicious  anemia  of  obtaining  enough  blood  for  the 

!  l°?r-  Physiol.,  1900,  vol.  xxv,  p.  6.         2  "Chlorosis,"  London,  1807,  p.  24. 
3  Zeitschr.  f.  klin.  Med.,  1894,  vol.  xxiv,  p.  500. 

267 


268 


DISEASES  OF  THE  BLOOD. 


examination.  The  blood  spread  out  in  a  film  over  the  finger  is 
transparent  rather  than  opaque,  and  its  fluidity  is  most  striking. 

Microscopical  examination  of  the  fresh  film  shows  excessive 
pallor  of  most  of  the  erythrocytes,  together  with  the  presence  of 
a  variable  number  of  cells  of  smaller  diameter  than  normal,  in 
the  average  case,  and  of  cells  decidedly  deformed  in  shape,  in 
severe  cases.  The  resistance  of  the  erythrocytes,  as  shown  by 
their  hypotonicity,1  is  increased.  The  practised  observer  can 
determine  at  first  glance  that  the  number  of  erythrocytes  is  not 
greatly  decreased,  except  in  an  occasional  case  in  which  the 
oligocythemia  may  be  so  marked  as  to  lead  him  to  infer  that  he  is 
dealing  with  a  well-defined  secondary  anemia. 

Coagulation  of  the  blood  drop,  in  spite  of  the 
Coagulation,  fact  that  hyperinosis  is  absent,  is  generally  very 
rapid  in  chlorosis — often  so  rapid  as  to  interfere 
with  the  technic  of  the  examination,  if  one  delays  during  this 
procedure. 

The  specific  gravity  of  the  whole  blood  is  more 
Specific  or  less  diminished,  the  degree  of  decrease  being 
Gravity,     closely  parallel  with  the  loss  of  hemoglobin. 

Lloyd  Jones,2  who  has  made  elaborate  researches 
concerning  this  subject,  believes  that  chlorotic  blood  exhibits  an 
exaggeration  of  the  fall  in  specific  gravity  which  occurs  in  healthy 
girls  at  about  the  age  of  puberty.  In  the  36  cases  studied  by 
this  author  the  specific  gravity  ranged  from  1.030  to  1.049,  these 
figures  corresponding  to  17  and  58  per  cent,  of  hemoglobin,  re- 
spectively, as  estimated  by  the  von  Fleischl  hemometer.  In  30 
cases  Hammerschlag 3  found  that  the  density  of  the  whole  blood 
averaged  1.045,  and  of  the  serum,  1.030. 

Most  observers  maintain  that  in  this  dis- 
Alkallnity.  ease  the  alkalinity  of  the  whole  blood  generally 
remains  normal,  or  suffers  but  a  trifling  diminu- 
tion, this  being  in  direct  contrast  to  the  condition  found  in  other 
forms  of  anemia,  in  which  the  fall  in  the  alkalinity  figure  is  usually 
pronounced.  Burmin,4  in  18  examinations  of  9  cases,  found  that 
it  ranged  between  128  and  200  mgm.  NaOH,  the  normal  figures 
of  this  investigator  being  182  to  218  mgm.  In  6  of  these  cases 
the  administration  of  iron  was  followed  by  a  marked  increase  in 
the  alkalinity  of  the  blood,  closely  paralleling  the  gain  in  hemo- 
globin and  erythrocytes.  On  the  other  hand,  Graeber 5  states  that 

1  Von  Limbeck,  loc.  cit. 

2  Loc.  cit.  3.Wien.  med.  Presse,  1894,  vol.  xliv,  p.  1068. 

4  Zeitschr.  f.  klin.  Med.,  1900,  vol.  xxxix,  p.  365. 

5  "Zur  klin.  Diag.  d.  Blutkrankheit.,"  Leipsic,  1890,  p.  289. 


CHLOROSIS. 


269 


in  many  cases  he  discovered  abnormally  high  alkalinity  figures, 
so  constantly,  indeed,  that  he  regarded  them  as  "  specific  for  this 
condition."  Funke's  studies,  reported  by  Dare,1  show  that  the 
alkalinity  is  diminished,  and  that  it  closely  corresponds  to  the 
color  index. 

The  decrease  in  the  percentage  of  hemoglobin 
Hemoglobin  is  usually  excessive  in  comparison  with  the  re- 
and         duction  in  the  number  of  erythrocytes,  this  dis- 
Erythrocytes.  proportionate  oligochromemia  being  the  most 
conspicuous  and  most  constant  feature  of  the 
changes  affecting  chlorotic  blood.    Naturally,  such  a  change 
gives  rise  to  very  low  color  indices.    This  statement  applies  only 
to  the  majority  of  cases,  for  a  low 


G 


a- 


0 


o 


o 
0  ® 

&  a 


0, 


0 


o 


Fig. 


color  index,  while  it  is  the  rule 
in  chlorosis,  and  is,  diagnostic- 
ally,  a  most  important  feature  of 
the  blood  picture,  is  by  no  means 
invariably  found — no  more  in- 
variably than  a  high  color  index 
in  pernicious  anemia.  To  illus- 
trate this  point,  of  106  consecu- 
tive cases  of  chlorosis  studied  by 
the  author,  49,  or  more  than  46 
per  cent.,  showed  an  index  below 
0.50,  the  average  for  the  series 
being  0.51,  the  maximum  1.01, 
and  the  minimum  0.22. 

The  average  loss  of  hemo- 
globin, as  evidenced  by  the  155 
cases  tabulated  below,  amounts 
to  about  53  per  cent.,  in  contrast 

to  which  stands  the  mean  average  erythrocyte  decrease,  which  is 
equivalent  to  about  23  per  cent.,  the  hemoglobin  loss  thus  averag- 
ing about  two-and-one-half  times  that  of  the  corpuscles.  -Indi- 
vidually, the  hemoglobin  percentage  ranged  in  these  cases  from 
12  to  87,  averaging  46.8,  and  the  count  of  erythrocytes  from 
1,720,000  to  5,600,000,  averaging  3,816,486.  On  account  of 
their  rather  close  correspondence,  it  is  interesting  to  compare 
with  these  figures  the  results  obtained  by  Cabot 2  in  109  cases 
and  those  of  Thayer3  for  63  cases.  Cabot's  cases  gave  the 
following  mean  averages:  hemoglobin,  41.2  per  cent.;  erythro- 

1  Johns  Hopkins  Hosp.  Bull.,  1903,  vol.  xiv,  p.  179.  2  Loc.  cit. 

3  Cited  by  Osier,  "American  Text-book  of  Theory  and  Practice  of  Medicine," 
Philadelphia,  1894,  vol.  ii,  p.  196. 


51. — Changes  in  the  Erythrocytes 
in. Chlorosis  (Triacid  Stain). 
Showing  a  general  decrease  in  the  diam- 
eter of  the  corpuscles,  striking  decolorization. 
and  moderate  poikilocytosis.  The  nucleated 
cell  near  the  center  of  the  field  is  a  normo- 
blast. 


270  DISEASES  OF  THE  BLOOD. 

cytes,  4,112,000,  with  individual  counts  ranging  from  1,932,000 
to  7,100,000.  In  Thayer's  series  the  hemoglobin  averaged  42.3 
per  cent,  and  the  erythrocyte  count  4,096,544.  Somewhat  lower 
figures  are  given  by  Bramwell,1  who  found  the  following  averages 
in  a  series  of  80  cases:  hemoglobin,  34  per  cent.,  or  from  10  to  60 
per  cent.;  erythrocytes,  3,437,300,  or  from  1,425,000  to  5,200,000 
per  c.mm.;  and  color  index,  0.49,  or  from  0.20  to  0.96. 

While  numerous  examples  may  be  found  of  typical  cases  of 
chlorosis  in  which  the  hemoglobin  estimate  and  erythrocyte  count 
resemble  those  commonly  occurring  in  pernicious  anemia  or  in 
the  secondary  anemias,  nothing  is  more  characteristic  of  chlorosis 
than  the  averages  above  mentioned.  The  great  difference  is 
between  chlorosis  and  pernicious  anemia,  the  index  usually  being 
high  and  the  corpuscular  loss  extreme  in  the  latter  disease.  As 
compared  with  the  secondary  anemias,  the  difference  is  too  slight 
and  its  occurrence  too  inconstant  to  enable  one  to  regard  it  with 
any  degree  of  certainty  from  a  clinical  standpoint.  Theoretically, 
in  secondary  anemia  the  hemoglobin  loss  is  fairly  proportionate 
to  the  erythrocyte  decrease,  thus  producing  color  indices  at  or 
somewhat  below  the  normal,  but  cases  of  secondary  anemia  having 
a  so-called  "chlorotic"  type  of  blood  are  far  too  common  to  render 
any  information  reliable  gained  by  a  simple  inquiry  into  the 
changes  affecting  the  erythrocytes  and  their  hemoglobin  content. 

TABLE  I.— HEMOGLOBIN  AND  ERYTHROCYTES  IN  155  CASES  OF 

CHLOROSIS. 

Hemoglobin                         Number  of  Erythrocytes  Number  of 

Percentage.                            Cases.  per  c.mm.  Cases. 

From  80-90                           5  Above  5,000,000  13 

70-80  11  From  4,000,000-1;, 000,000  63 

60-70  17  u 

»    5o-6o  35  3,000,000-4,000,000  49 

"    40-50  24  "     2,000,000-3,000,000  28 

"    30-40  25  "     1,000,000-2,000,000   2 

"    20-30..  28 

"    10-20  10 

Average,     46.8  per  cent.  Average,     3,816,486  per  c.mm. 

Maximum,  87.0  "     "  Maximum,  5,600,000  "  " 

Minimum,  12.0   "     "  Minimum,  1,720,000  "  " 

The  most  conspicuous  change  to  be  observed  in  the  stained 
film  of  chlorotic  blood  is  the  presence  of  large  numbers  of  under- 
sized, pale  erythrocytes,  such  cells  usually  being  so  numerous 
that  one  is  forcibly  impressed  with  the  fact  that  there  must  be  a 
general  decrease  in  the  average  diameter  of  all  the  erythrocytes 
in  the  field.  As  a  rule,  this  decrease  in  size  involves  a  large 
number  of  corpuscles  moderately,  rather  than  a  few  to  an  ex. 

1  "Anemia,"  London,  1899,  p.  35. 


CHLOROSIS. 


271 


treme  degree,  and  therefore,  except  in  severe  cases  associated 
with  marked  oligocythemia,  striking  examples  of  microcytosis  are 
wanting.  This  alteration  is  just  the  opposite  of  what  is  generally 
found  in  pernicious  anemia,  for  in  this  disease  a  tendency  to- 
ward an  increase  in  the  average  diameter  of  the  erythrocytes, 
frequently  in  association  with  the  presence  of  many  extremely 
small  microcytes,  is  the  rule.  If  well  defined,  this  feature  of  the 
blood  changes  carries  a  certain  amount  of  diagnostic  significance, 
although  it  cannot  be  distinguished  in  every  case  of  chlorosis, 
since  in  some  the  diameter  of  the  erythrocytes  appears  to  be  un- 
altered, while  in  others  the  deformities  of  size  may  so  affect  the  cells 
that  the  blood  picture  resembles  that  of  a  severe  secondary  anemia. 

The  pallor  of  the  erythrocytes,  shown  by  their  feeble  reaction 
toward  the  plasma  stain,  is  at  once  apparent.  The  great  majority 
of  the  cells  are  affected  alike,  being  pale,  often  quite  colorless  in 
the  center,  and  gradually  becoming  of  darker  color  toward  the 
periphery,  in  which  a  certain  amount  of  hemoglobin  still  remains. 
This  portion  of  the  cell  is  usually  well  stained,  so  that  the  cor- 
puscles frequently  appear  as  hoops  or  rings;  some,  however,  do 
not  show  even  this  narrow  hemoglobin-filled  zone,  being  practi- 
cally decolorized  throughout.  Stroma  degeneration,  as  shown  by 
the  changes  described  by  Maragliano,  is  not  demonstrable  in  the 
average  case  of  moderate  severity,  but  this  process  has  been  ob- 
served in  occasional  cases  of  high  grade.  Polychromatophilia, 
except  in  cases  of  the  latter  class,  does  not  occur. 

Basophilic  granulations  in  the  erythrocytes  are  not  present  in 
this  condition,  according  to  Grawitz,1  a  finding  which  the  author 
has  substantiated.2  Stengel,3  on  the  contrary,  found  them  in  11  of 
18  chlorotics. 

Deformities  of  shape  are  not  noticeable,  as  a  rule,  except  in 
the  severer  types  of  the  disorder.  In  such  cases,  in  which  both 
the  hemoglobin  and  the  cellular  losses  are  excessive,  poikilo- 
cytosis  may  be  very  striking — as  great,  in  fact,  as  in  any  blood 
disease,  not  excepting  pernicious  anemia.  Poikilocytes,  should 
they  occur,  are  almost  invariably  of  small  size. 

Nucleated  erythrocytes  are  very  rare.  In  the  average  case 
they  are  usually  sought  for  in  vain,  and  even  in  the  severer  forms 
of  chlorosis  these  cells  are  not  numerous.  Erythroblasts  con- 
forming to  the  normoblastic  type  are  found  almost  exclusively; 
megaloblasts,  although  they  are  seen  now  and  then,  are  extremely 
uncommon,  and  have  never  been  found  in  a  large  relative  or 
absolute  proportion  to  the  other  form  of  nucleated  erythrocytes. 


1  Loc.  cit.  2  Amer.  Med.,  1903,  vol.  v,  p.  571. 

3  Amer.  Jour.  Med.  Sci.,  1902,  vol.  cxxii,  p.  873. 


272 


DISEASES  OF  THE  BLOOD. 


TABLE  II.— NUMBER  OF  LEUCOCYTES  IN  155  CASES  OF 
CHLOROSIS. 


The  number  of  leucocytes  per  c.mm.  is, 
Leucocytes,  as  a  rule,  normal  in  the  typical  case  of  chloro- 
sis. If  leucocytosis  occurs,  as  it  does  occasion- 
ally, it  should  be  attributed  to  some  hidden  or  frank  complication; 
if  leucopenia  exists,  as  it  sometimes  does,  it  may  nearly  always 
be  regarded  as  a  sign  of  the  severity  of  the  disease,  since  it  is 
rarely  met  with  except  in  cases  in  which  the  hemoglobin  and  ery- 
throcyte losses  are  decidedly  marked.  The  mean  average  number 
of  leucocytes  in  the  155  cases  of  chlorosis  to  which  reference  has 
already  been  made  (Table  II)  is  6457  Per  c.mm.,  or  approximately 
the  same  as  the  average  count  of  these  cells  in  normal  blood. 
Counts  as  low  as  800  and  as  high  as  21,000  were  made  in  this  series; 
and  in  18  of  the  cases  (or  11.6  per  cent.)  the  increase  was  suf- 
ficiently in  excess  of  the  normal  standard  to  justify  the  application 
of  the  term  leucocytosis — that  is,  it  was  in  excess  of  10,000.  These 
figures  do  not  differ  materially  from  those  of  Cabot  and  of  Thayer, 
alluded  to  above,  Cabot's  counts  in  104  cases  averaging  7400,  and 
Thayer's  estimates  in  63  cases  being  but  slightly  higher — 7485. 

Relative  lymphocytosis,  usually  marked  in  relation  to  the  se- 
verity of  the  case,  is  a  common,  but  not  a  constant,  qualitative 
change.  It  occurs  in  both  mild  and  severe  cases,  but  is  much 
more  common  in  the  latter.  In  the  author's  experience  this  in- 
crease involves  chiefly  the  larger  forms  of  these  cells,  both  the 
non-granular  mononuclear  cells  with  spherical  nuclei  and  the  so- 
called  "transitional"  forms  with  indented  nuclei;  striking  in- 
crease in  the  last-named  variety  of  cells  was  a  notable  differential 
change  in  a  large  proportion  of  the  37  cases  listed  in  Table  III. 
In  many  of  the  cases  in  this  series  the  large  and  small  lympho- 
cytes together  made  up  from  45  to  as  high  as  67.5  per  cent,  of 
all  varieties  of  leucocytes,  the  percentage  of  large  forms  being 
repeatedly  estimated  at  20  or  30,  and  even  40,  in  one  instance. 

Deviations  from  normal  in  the  relative  percentage  of  polynu- 
clear  neutrophiles  are  governed  by  the  behavior  of  the  lympho- 
cytes, low  differential  counts  of  the  former  type  of  cells  accom- 


Leucocytes 

PER  C.MM. 

Above  20,000  

From  15,000-20,000   

"  10,000-15,000   

"  5,000-10,000   

Below  5,000  

Average,       6,457  Per  c.mm. 
Maximum,  21,000  "  " 
Minimum,      800  "  " 


Number  of 
Cases. 


3 

14 
104 

33 


CHLOROSIS. 


273 


panying  high  percentages  of  the  latter,  and  vice  versa.  Should 
leucocytosis  exist,  it  is  of  the  pure  polynuclear  neutrophile  type. 

The  eosinophiles  are  notably  decreased,  both  absolutely  and 
relatively.  The  author  has  never  found  an  increase  of  these  cells 
in  chlorosis,  although  considerable  pains  were  taken  to  verify  the 
statements  made  by  some  writers  that  this  variety  of  leucocytes 
is  occasionally  observed  to  be  greatly  above  normal  in  this  con- 
dition. Eosinophiles  were  absent  entirely  in  more  than  seven- 
tenths  of  all  the  cases  collected  in  Table  III,  and  were  never  found 
to  exceed  two  per  cent,  of  all  the  forms  of  leucocytes. 


TABLE  III.— QUALITATIVE  CHANGES  IN  THE  LEUCOCYTES  IN 
37  CASES  OF  CHLOROSIS  AT  THE  FIRST  EXAMINATION. 


Case  No. 

Small  Lympho- 
cytes. 

Large  Lympho- 

CYTES. 

Polynuclear 
Neutrophiles  . 

Eosinophiles. 

Myel 

OCYTES. 

i 

16.0 

6.0 

76.0 

2.0 

O 

2 

11 .0 

3-° 

85-5 

°-5 

O 

3 

20.0 

3-5 

75-° 

1. 5 

O 

4 

25.0 

3-° 

72 .0 

o.o 

O 

5 

19-5 

20.5 

60.0 

o.o 

O 

6 

22.5 

15.0 

62.5 

0.0 

O 

7 

20.5 

19.0 

60.5 

0.0 

O 

8 

32.2 

17.8 

50.0 

0.0 

O 

9 

25-5 

16.0 

57-5 

1.0 

O 

IO 

18.5 

12.0 

69-5 

0.0 

O 

ii 

18.0 

10. 0 

72 .0 

0.0 

O 

12 

17.0 

21-5 

61-5 

0.0 

O 

i3 

i9-5 

17.0 

63.0 

0-5 

O 

14 

22.0 

i4-5 

63-5 

0.0 

O 

i5 

7-5 

12.4 

8o.i 

0.0 

O 

16 

i9-3 

21. 1 

59-6 

o.o 

O 

i7 

18-5 

16.0 

65-5 

0.0 

O 

18 

18.0 

16.0 

65.0 

1 .0 

O 

i9 

i8-3 

19.0 

61 .0 

i-7 

O 

20 

i5-5 

24-5 

60.0 

0.0 

O 

21 

26.0 

21.0 

53-o 

0.0 

O 

22 

12.0 

30.0 

58-0 

0.0 

O 

23 

i3-5 

12-5 

73-5 

o-5 

O 

24 

14.0 

i5-9 

70.1 

0.0 

O 

25 

i7-5 

14.0 

68.5 

0.0 

O 

26 

15-0 

17.0 

68.0 

0.0 

O 

27 

20.5 

ii-5 

68.0 

0.0 

O 

28 

20.3 

12.7 

67.0 

0.0 

O 

29 

31.0 

9.0 

60.0 

0.0 

O 

3° 

35-9 

6.0 

58-0 

0. 1 

O 

31 

24.0 

2.0 

74.0 

0.0 

O 

32 

27-5 

40.0 

32.0 

o-5 

O 

33 

26.0 

15-0 

56.0 

1.0 

2 

34 

24.0 

26.0 

50.0 

0.0 

O 

35 

22.0 

6.0 

72 .0 

0.0 

O 

36 

24-5 

14-5 

61 .0 

0.0 

O 

37 

6.0 

32-0 

59-o 

0.0 

3 

Average:  20.1 

i5-5 

64.0 

0.31 

0.13 

18 


DISEASES  OF  THE  BLOOD. 


Diagnosis. 
Color. 

Coagulation. 
Specific  gravity. 
Hemoglobin. 


Erythrocytes. 


Exceptionally,  small  percentages  of  myelocytes  may  be  en- 
countered, as  a  rule  only  in  cases  of  a  severe  character.  These 
cells  arc  ordinarily  present  in  not  more  than  six  per  cent,  of  all 
cases,  and  their  relative  proportion  to  the  other  forms  of  leuco- 
cytes is  always  trifling,  being  rarely  over  one  or  two  per  cent. 

In  the  great  majority  of  cases  it  has  been  gen- 
Blood        erally  observed  that  the  number  of  plaques  is 
Plaques.     considerably  in  excess  of  normal.    It  appears 
that  these  elements  are  especially  numerous  in 
blood  which  clots  rapidly. 

The  changes  in  the  blood  associated  with  the 
well-defined  case  of  chlorosis  may  be  summarized 
as  follows  : 

Pale  and  watery. 
Usually  rapid. 
Decreased. 

Marked  absolute  decrease,  in  most  instances 
relatively  greater  than  the  loss  of  erythrocytes, 
thus  producing  a  low  color  index. 
Moderately  decreased,  ordinarily  to  about 
4,000,000  per  c.mm.  Counts  of  3,000,000 
or  lower  are  common  in  severe  cases.  Ery- 
throblasts  very  rare;  if  present,  cells  of  the 
normoblastic  type  invariably  predominate. 
General  decrease  in  the  average  diameter  of 
the  erythrocytes.  In  severe  cases  microcy- 
tosis  may  be  marked. 

Poikilocytes  not  numerous,  except  in  severe 
cases. 

Polychromatophilia  rare. 
Usually  normal  in  number. 
Relative  lymphocytosis  common. 
Small  percentages  of  myelocytes,  only  in  severe 
cases. 

Eosinophiles  notably  decreased. 
Increased  in  number. 
He  who  attempts  the  diagnosis  of  chlorosis  solely  by  the  blood 
examination  is  indeed  a  rash  clinician.  This  point  cannot  be 
emphasized  too  strongly,  that  there  is  no  blood  picture  peculiar 
to  this  condition,  since  changes  precisely  similar  to  those  seen  in 
many  a  case  of  typical  chlorosis  are  often  observed  in  the  secondary 
anemias,  especially  in  those  dependent  upon  such  factors  as  syph- 
ilis, septicemia,  malignant  disease,  and  chronic  renal  lesions. 
Futhermore,  rare  cases  of    chlorosis  with    typical  symptoms 


Leucocytes. 


Plaques. 


CHLOROSIS. 


275 


have  been  reported  in  which  no  alterations  in  the  blood  were 
discoverable  by  ordinary  clinical  methods.  In  these  cases,  mis- 
termed  "  pseudo-chlorosis,"  a  diminished  volume  of  plasma  may 
mask  the  blood  impoverishment  (Lloyd  Jones1),  or  this  oligo- 
plasmia  may  be  combined  with  both  plasma  and  cellular  hy- 
dremia (Biernacki2),  the  dropsical  erythrocytes  being  actually 
deficient  in  hemoglobin,  although  the  hemoglobin  and  erythrocyte 
estimates  of  the  whole  blood  remain  normal. 

The  blood  changes  enumerated  above  (especially  such  features 
as  a  low  color  index,  the  general  decrease  in  the  diameter  of  the 
erythrocytes,  the  absence  or  scantiness  of  erythroblasts,  and  the 
normal  number  of  leucocytes  associated  with  relative  lymphocytosis 
and  a  decrease  of  the  eosinophiles)  are  not  then,  pathognomonic,  but 
simply  highly  suggestive  of  the  disease  under  discussion,  in  view  of 
which  fact  it  becomes  essential  to  seek  for  other  clinical  signs 
and  to  consider  them  carefully  in  connection  with  the  blood  find- 
ings. One  of  the  most  important  points  which  should  be  borne 
in  mind  is  the  fact  that  chlorosis  is  practically  confined  to  females, 
usually  those  in  early  womanhood,  at  or  near  the  period  of  puberty. 
Chlorosis  is  about  as  compatible  with  the  male  sex  as  is  pregnancy 
— the  so-called  "male  chlorosis"  is  nothing  more  than  a  diagnostic 
myth.  Osier3  remarks  that  in  girls  in  whom  the  disease  occurs 
early  in  their  teens  precocity  and  almost  premature  appearance  of 
the  menses  are  likely  to  exist.  A  large  proportion  of  those  in 
whom  the  disease  develops  later  in  life  complain  of  scantiness  or 
total  suppression  of  the  menstrual  flow  and  of  dysmenorrhea,  these 
symptoms  being  especially  common  in  chlorotics  in  the  early 
twenties  or  thereabouts. 

The  question  of  heredity  also  is  of  some  diagnostic  value,  for 
it  has  been  frequently  noted  that  the  disease  exists,  for  instance, 
in  two  or  more  sisters,  the  statement  being  elicited  upon  further 
inquiry  that  their  mother  suffered  from  chlorosis  at  an  earlier 
period.  Thus,  Allbutt 4  speaks  of  meeting  in  his  consulting-room 
the  chlorotic  daughters  of  women  whom  years  before  he  had 
treated  for  the  same  disorder. 

Among  the  other  manifestations  of  the  disease  to  which  atten- 
tion should  be  paid  the  following  are  the  more  important :  a  pecu- 
liar greenish-yellow  color  of  the  complexion  and  blanching  of  the 
mucous  membranes  (except  in  those  rare  instances  of  chlorosis 
florida,  in  which  the  color  is  high);  the  occurrence  of  various 
gastro-intestinal  disturbances,  of  edema  of  the  face  and  lower 


1  Loc.  cit.. 

2  Zeitschr.  f.  klin.  Med.,  1894,  vol.  xxiv,  p.  500.  3  Loc.  cit, 
4  "  System  of  Medicine,"  London  and  New  York,  1898,  vol.  vi,  p.  483. 


276 


DISEASES  OF  THE  BLOOD. 


limbs,  of  vertiginous  attacks,  and  of  dyspnea  upon  physical  exer- 
tion; and  the  presence  of  systolic  basic  heart  murmurs  and  a 
venous  hum  most  distinctly  audible  over  the  great  vessels  of  the 
neck.  Slight  enlargement  of  the  thyroid  gland,  frequently  asso- 
ciated with  Joffroy's  sign  (absence  of  horizontal  wrinkling  of  the 
skin  of  the  forehead  and  of  upward  curving  of  the  eyebrows  when 
the  patient  glances  suddenly  at  the  ceiling  without  elevating  her 
head),  is  a  physical  sign  which  should  always  make  one  suspicious 
of  chlorosis. 

The  distinctions  between  chlorosis  and  pernicious  anemia,  as 
shown  by  the  blood  examination,  will  be  described  under  the 
latter  disease.    (See  p.  289.) 

II.  PERNICIOUS  ANEMIA. 

Lorrain  Smith's  experiments1  argue  a  de- 
General     crease,  averaging  48  per  cent.,  in  the  total  oxygen 
Features,    capacity  of  the  blood,  and  also  show  that  the 
blood  volume  fluctuates  greatly  in  different  cases. 
Any  decided  increase,  however,  is  at  variance  with  both  the  clini- 
cal and  the  postmortem  findings. 

Diminution  in  the  albumin  of  the  whole  blood,  due  chiefly  to 
the  cellular  poverty,  is  a  conspicuous  change,  the  dry  residue  in 
extreme  instances  amounting  to  but  one-half  of  the  normal  figure.2 
The  albumin  of  the  blood  serum  is  also  diminished,3  but  not  greatly 
— a  point  of  difference  between  Addisonian  and  secondary  anemia, 
since  in  severe  types  of  the  latter  the  serum  albumin  is  strikingly 
subnormal. 

In  marked  cases  of  pernicious  anemia  it  is 
Appearance  sometimes  almost  impossible  to  obtain  from  a 
of  the       puncture  of  the  finger-tip  a  sufficient  quantity  of 
Fresh  Blood,  blood  for  an  ordinary  clinical  examination,  owing 
to  the  bloodlessness  of  the  superficial  vessels. 
This  fact  naturally  prompts  the  query,  Does  an  actual  reduction 
in  blood  volume  or  oligemia  exist  in  such  an  instance,  or  can  the 
dryness  of  the  superficial  tissues  be  attributed  to  vasomotor  dis- 
turbances causing  an  unequal  distribution  of  the  blood  mass,  in 
favor  of  the  internal  viscera  and  deeper  circulation  ?    In  a  patient 
in  whom  puncture  of  the  finger  fails  to  give  the  requisite  amount 
of  blood,  the  lobe  of  the  ear  will  generally  be  found  to  yield  a 
drop  of  sufficient  size.    But  even  this  very  vascular  part  of  the 

1  Loc.  cit. 

2  Gumprecht  and  Stintzing,  Deutsch.  Arch.  f.  klin.  Med.,  1894,  vol.  liii,  p.  265. 

3  Diabella,  ibid.,  1806,  vol.  lvii,  p.  302. 


PERNICIOUS  ANEMIA. 


277 


body  may  in  extreme  cases  seem  practically  bloodless.  The 
writer  recalls  a  case  of  fatal  anemia  in  which,  in  order  to  secure 
a  drop  of  blood  large  enough  to  fill  the  lumen  of  an  erythrocy- 
tometer  only  to  the  0.5  graduation,  it  was  necessary  to  open  a 
small  superficial  vessel  of  the  scalp,  repeated  deep  punctures  of 
the  fingers,  toes,  and  ear-lobes  having  given  negative  results. 

The  drop  as  it  emerges  from  the  puncture  wound  is  exceed- 
ingly pale,  thin,  and  hydremic,  lacking  the  characteristic  opac- 
ity of  healthy  blood,  and  being  of  a  fluidity  and  general  color 
which  have  been  likened  to  those  of  meat- washings.  In  an  oc- 
casional instance  the  color  of  the  blood  may  be  practically  normal, 
or,  rarely,  of  a  brownish-red  or  chocolate  tint;  but,  as  a  rule,  it 
resembles  a  watery,  pinkish  fluid,  deficient  both  in  depth  of  color 
and  in  density.  It  has  been  frequently  observed  that,  after  having 
stood  for  a  short  length  of  time,  the  drop  shows  a  tendency  to 
separate  into  two  more  or  less  distinct  parts,  consisting  of  a  dark 
stratum  of  corpuscles  and  a  clear,  watery-looking  layer  of  plasma ; 
or  it  may  be  irregularly  mottled  at  different  points,  as  if  the  cor- 
puscles had  become  concentrated  in  isolated,  compact  groups  in 
various  parts  of  the  plasma,  thus  producing  the  effect  of  alternating 
dark  and  light  areas  distributed  through  the  drop. 

Microscopical  examination  of  the  fresh  film  shows  a  great  re- 
duction in  the  number  of  the  erythrocytes,  together  with  the  pres- 
ence of  many  forms  of  these  cells  which  exhibit  every  possible 
variation  in  size  and  in  shape.  The  color  of  the  individual  eryth- 
rocyte varies,  some  being  normally  dark  and  well  colored,  while 
others  appear  as  mere  washed-out  rings  or  "phantoms."  In 
some  of  the  cells  the  hemoglobin  appears  to  be  quite  Evenly  dis- 
tributed throughout  the  stroma,  so  that  their  typical  biconcav- 
ity  is  obliterated.  The  endoglobular  degenerative  changes  and 
those  structural  alterations  denoting  total  necrosis  of  the  eryth- 
rocytes, previously  described,  may  be  demonstrated  with  great 
clearness  in  this  condition.  Rouleaux  formation  is  either  entirely 
absent,  or  incomplete  and  atypical. 

The  erythrocytes  are  abnormally  vulnerable,  as  shown  by  their 
increased  isotonicity1  and  by  the  readiness  with  which  their  con- 
tained hemoglobin  crystallizes.2  Von  Jaksch's  analyses 3  point  to 
a  decided  relative  excess  of  cellular  albumin. 

Owing  to  the  extreme  oligocythemia  common  in  pernicious 
anemia,  it  is  advisable  in  making  the  films  to  use  a  somewhat 
larger  drop  of  blood  than  is  chosen  for  making  ordinary  spreads, 

1  Von  Limbeck,  loc.  cit. 

2  Copeman,  Brit.  Med.  Jour.,  1901,  vol.  i,  p.  161. 

3  Zeitschr.  f.  klin.  Med.,  1893,  vol.  xxiii,  p.  187. 


278 


DISEASES  OF  THE  BLOOD. 


so  that  the  field  will  not  contain  such  a  pronounced  scarcity  of 
cellular  elements. 

The  obvious  fluidity  of  the  blood,  the  defici- 
Coagulation.  ency  of  the  fibrin  network,  and  the  slowness  with 
which  coagulation  occurs  are  marked  features  of 
this  disease.  In  fact,  in  some  cases  coagulation  may  be  said  not  to 
occur  at  all,  according  to  the  experiments  of  Hayem1  and  others 
of  the  French  school,  as  in  the  case  quoted  by  Lenoble,2  in  which 
no  clotting  of  a  sample  of  arterial  blood  was  observed  even  after 
a  lapse  of  seventy-two  hours  after  its  withdrawal  from  the  vessels. 
Many  authors  attribute  considerable  diagnostic  value  to  this 
absence  of  clotting,  and  others  go  so  far  as  to  state  that  it  ren- 
ders a  patient  suffering  with  pernicious  anemia  especially  prone 
to  troublesome  hemorrhages,  even  from  a  slight  finger-prick — an 
accident  which  must  be  extremely  rare,  however,  for  it  practically 
never  complicates  an  ordinary  clinical  examination. 

The  density  of  the  whole  blood  is  much 
Specific      below  the  normal  standard,  specific  gravities  as 
Gravity.     low  as  1.027  having  been  reported.    It  is  to 
be  recalled  that  in  cases  with  a  high  color  index 
erroneous  results  may  occur  from  attempting  to  estimate  the 
hemoglobin  percentage  by  Hammerschlag's  table  of  equivalents, 
since  the  hemoglobin,  in  reality,  is  somewhat  higher  than  the 
percentages  corresponding  to  the  specific  gravity  figures.  (See 

p-  m;) 

Up  to  the  present  time  the  reaction  of  the 
Alkalinity,  blood  in  pernicious  anemia  has  not  been  very 
thoroughly  studied,  but  the  work  already  accom- 
plished is  sufficient  to  show  that  the  alkalinity  is  much  diminished, 
as  in  other  severe  anemias.  That  it  may  be  strikingly  below 
normal  is  shown  by  a  case  reported  by  Waldvogel,3  who  in  one 
case  estimated  the  alkalinity  figure  at  40  mgm.,  using  Salkowski's 
method.  This  author  has  determined  that  the  normal  alkalinity 
for  men  ranges  from  350  to  400  mgm.,  and  for  women  from  300 
to  350  mgm. 

Both  the  percentage  of  hemoglobin  and  the 
Hemoglobin  number  of  erythrocytes  are  greatly  diminished, 
and         the  former,  as  a  general  rule,  relatively  less  so 
Erythrocytes,  than  the  latter.    Thus,  inasmuch  as  the  individual 
corpuscles  contain  often  a  normal  or  even  an  ex- 
cessive amount  of  hemoglobin,  it  follows  that  high  color  indices 
are  common — common  but  by  no  means  constant,  as  seems  to  be 

1  Loc.  cit.  2  "Charact.  semeiol.  du  caillot  et  du  serum,"  Paris,  1898. 

3  Deutsch.  med.  Wochenschr.,  1900,  vol.  xxvi,  p.  685. 


tIBRARY 


CHART  I. 


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PERNICIOUS  ANEMIA. 
Red,  Hemoglobin.  Black,  Erythrocytes.  Blue,  Leucocytes. 


PERNICIOUS  ANEMIA.  279 

the  current  impression  among  many  students,  for  although  it  is 
true  that  while  the  average  color  index  is  about  i  .00  in  pernicious 
anemia  cases,  the  same  statement  cannot  always  be  applied  to 
the  individual  case.  The  author's  series  of  81  cases  (Table 
IV)  showed,  at  the  first  examination,  hemoglobin  percentages 
varying  from  a  minimum  of  10  to  a  maximum  of  70,  with  a  mean 
average  of  27.1;  the  color  index  of  these  cases  averaged  0.99. 
During  remissions,  as  the  erythrocytes  increase,  it  is  common  to 
find  low  indices,  this  peculiarity  being  especially  conspicuous 
should  the  improvement  in  the  patient's  condition  be  rapid, 
since  in  such  instances  the  corpuscular  increase  is  relatively  much 
more  rapid  than  the  gain  in  hemoglobin.  In  cases  in  which  im- 
provement takes  place  more  slowly,  the  color  index  is  likely  to 
remain  higher,  for  here  the  corpuscles  and  the  hemoglobin  are 
more  prone  to  increase  proportionately  along  parallel  lines. 

TABLE  IV.— HEMOGLOBIN  AND  ERYTHROCYTES  IN  81  CASES 
OF  PERNICIOUS  ANEMIA. 

Hemoglobin  Number  of  Erythrocytes  Number  of 

Percentage  Cases.  per  cmm.  Cases. 

From  60-70   1  Above  3,000,000   2 

"    50-60  2  From  2,000,000-3,000,000  13 

"    4°_5°  4  "     1,000,000-2,000,000  41 

"    30-40  16  "       500,000-1,000,000  23 

20-30  30  Below    500,000    2  I 

"    10-20  28 

Average,     27.1  per  cent.  Average,     1,361,777  per  cmm. 

Maximum,  70.0  "      "  Maximum,  3,240,000  "  " 

Minimum,  10.0  "      "  Minimum,     450,000   "  " 

The  oligocythemia  is  most  striking,  counts  of  from  1,000,000 
to  2,000,000  erythrocytes  per  cmm.  being  not  uncommon  when 
the  patient  first  comes  under  observation,  the  number  of  cells 
frequently  diminishing  to  about  750,000  or  even  500,000  later 
during  the  course  of  the  disease.  In  Quincke's  often-quoted 
case  the  remarkable  count  of  143,000  per  cmm.  was  observed 
just  before  the  death  of  the  patient,  an  instance  which  is  almost 
paralleled  by  a  case  recorded  by  Hills,1  in  which  the  erythrocyte 
count  fell  to  155,760  one  day  before  death.  In  the  series  just 
mentioned  (Table  IV)  the  count  of  erythrocytes  per  cmm. 
averaged  1,361,777,  ranging  between  450,000  and  3,240,000; 
this  represents  an  average  loss  in  corpuscular  matter  of  some- 
what less  than  75  per  cent.,  the  greatest  decrease  amounting  to 
91  per  cent,  of  normal — a  much  more  striking  oligocythemia  than 
is  found  in  any  other  form  of  anemia.  Thirty  per  cent,  of  the 
cases  showed  a  count  of  1,000,000  or  lower. 


1  Boston  Med.  and  Surg.  Jour.,  1898,  vol.  cxxxix,  p.  542. 


280 


DISKASKS   OF   XII I :  BLOOD. 


Periods  of  temporary  increase  in  the  hemoglobin  and  erythro- 
cytes, followed  sooner  or  later  by  relapses,  are  commonly  observed, 
the  gain  during  such  periods  sometimes  being  very  pronounced. 
Thus,  in  one  of  the  cases  tabulated  above  a  gain  of  more  than 
2,500,000  erythrocytes  to  the  c.mm.  was  noted  during  six  weeks' 
time  with  a  subsequent  loss  of  over  1,000,000  cells  in  the  fol- 
lowing eight  days,  the  color  index  during  this  time  ranging  from 
1.25  to  0.74.  Such  stages  of  remission  may  or  may  not  follow 
vigorous  treatment  by  arsenic  or  other  medicaments.  Elder,1 
by  the  use  of  antistreptococcic  serum,  caused  a  gain  of  4,000,000 
cells  per  c.mm.,  while  DeWitt,1  by  the  same  means,  caused  an  in- 
crease in  hemoglobin 
rr~^  from  30  to  90  per  cent. 

and  in  erythrocytes 
from  1,000,000  to 
4,960,000  in  three 
weeks'  time. 

These  periods  of 
improvement  in  the 
condition  of  the  blood 
are  generally  associ- 
ated with  an  amelio- 
ration of  the  other 
clinical  manifestations 
of  the  disease,  the  pa- 
tient's general  condi- 
tion improving  so  sub- 
stantially that  he  be- 
gins to  consider  him- 
self on  the  high  road 
to  recovery,  but  in  the 
course  of  time  the  old 
symptoms  return,  and 

the  characteristic  blood  picture  again  becomes  evident.  In  most 
cases  death  is  preceded  by  extreme  oligochromemia  and  oligo- 
cythemia, the  hemoglobin  often  falling  to  15  or  20  per  cent,  of 
normal  and  the  erythrocyte  count  declining  to  750,000  or  less;  in 
some  cases,  however,  these  losses  are  not  so  marked,  and  the  count 
does  not  fall  below  1,500,000  during  the  whole  course  of  the  disease. 

A  prominent  characteristic  of  the  blood  in  pernicious  anemia 
is  the  wide  dissimilarity  in  the  size  of  the  erythrocytes,  due  to  the 
presence  of  large  numbers  of  megalocytes  and  microcytes;  so 

1  Cited  by  Packard  and  Willson,  Amer.  Jour.  Med.  Sci.,  1902,  vol.  exxiv, 
p.  1015. 


Fig.  52. — Changes  in  the  Erythrocytes  in  Pernicious 
Anemia  (Ehrlich's  Triacid  Stain). 
Showing  a  general  increase  in  the  diameter  of  the  cor- 
puscles, and  marked  poikilocytosis.    The  nucleated  cell  in 
the  right  of  the  field  is  a  megaloblast. 


PERNICIOUS  ANEMIA. 


28l 


striking  may  this  feature  of  the  blood  picture  be  that  it  is  some- 
times difficult  to  find  any  two  cells  in  the  same  field  of  the  micro- 
scope which  are  of  the  same  diameter.  In  the  great  majority  of 
cases  it  will  be  found  that  the  megalocytes  distinctly  outnumber 
the  microcytes,  to  such  an  extent  and  in  so  large  a  proportion 
of  cases  that  some  writers  consider  this  change  an  almost  con- 
stant blood  finding  in  this  disease.  Large  erythrocytes,  measur- 
ing slightly  below  or  above  10  p  in  diameter,  are  very  common, 
while  those  measuring  in  the  neighborhood  of  15  p  or  even  20  fi 
are  met  with  more  rarely.  Undersized  erythrocytes,  about  3  or 
4  n  in  diameter,  are  also  numerous,  but,  as  remarked  above, 
much  less  so  than  those  of  larger  size.  The  presence  of  small, 
dark-colored,  spherical  microcytes  of  this  size  (the  so-called 
"Eichhorst's  corpuscles"),  once  regarded  as  pathognomonic  of 
pernicious  anemia,  is  neither  constant  nor  diagnostic  of  this  dis- 
ease, since  they  are  found  in  many  other  anemic  conditions,  and 
are  absent  in  a  large  proportion  of  cases  of  true  pernicious  anemia. 
The  fact  that,  of  these  alterations  in  the  size  of  the  erythrocytes, 
megalocytosis  predominates,  constitutes  a  sign  of  valuable  diag- 
nostic significance. 

Poikilocytosis,  to  a  more  or  less  marked  degree,  is  constantly 
observed,  the  conspicuousness  of  the  deformities  being  in  some 
cases  extreme,  while  in  others  the  change  is  a  less  notable  feature. 
While  marked  poikilocytosis  usually  goes  hand  in  hand  with 
excessive  diminution  in  the  number  of  erythrocytes  and  in  the 
amount  of  hemoglobin,  the  association  of  these  three  changes 
cannot  be  invariably  counted  upon,  for  in  some  cases,  in  spite  of 
the  fact  that  both  oligocythemia  and  oligochromemia  are  marked, 
deformities  in  the  shape  of  the  corpuscles  are  but  trifling.  All 
varieties  of  erythrocytes,  small,  large,  nucleated,  and  non-nu- 
cleated, may  be  deformed,  so  that  the  size  of  the  poikilocytes 
varies  from  that  of  the  smallest  microcyte  to  that  of  the  largest 
megalocyte.  The  kinds  of  deformity  are  of  infinite  variety,  but 
it  is  still  possible  to  designate  certain  well-defined  forms  which 
are  especially  common  in  this  disease,  these  being  the  horseshoe 
form  (Litten)  and  the  oval  form  (Cabot),  both  of  which  varieties, 
while  by  no  means  peculiar  to  this  condition,  are  found  so  fre- 
quently and  in  such  abundance  in  pernicious  anemia  that  their 
presence  in  the  blood  is  at  least  highly  suggestive.  Of  these 
two  forms,  the  elongated,  oval  erythrocyte  is  found  more  con- 
stantly, and  has  been  described  in  but  a  few  other  conditions. 
The  author  has  been  struck  with  the  predominance  of  cells  of 
this  sort  in  three  consecutive  cases  of  purpura  haemorrhagica, 
in  one  of  which  the  deformity  was  so  marked  that  scarcely  a 


282 


DISKASKS   OF   TIIK  BLOOD. 


single  normally  shaped  erythrocyte  could  be  found  in  certain 
fields  of  the  microscope.  Cabot1  cites  Greene  as  noticing  the 
same  change  in  the  blood  of  two  patients  in  whom  the  tentative 
diagnosis  of  epidemic  dropsy  had  been  made.  In  addition  to 
these  well-defined  varieties,  many  cells  of  other  shapes,  also  met 
with  in  other  severe  anemias,  are  observed,  notably  those  resemb- 
ling the  form  of  a  sausage,  a  spindle,  or  a  club.  (See  Fig.  52, 
p.  280.) 

In  the  stained  specimen  the  principal  point  of  interest  is  the 
presence  of  nucleated  erythrocytes,  upon  the  character  of  which 
the  diagnosis  of  pernicious  anemia  must  depend.  Erythroblasts 
are  always  to  be  found  in  this  disease  at  some  stage  of  its  course.2 
During  remissions,  however,  they  may  temporarily  disappear. 
Megaloblasts  are  of  much  greater  clinical  significance  than  nor- 
moblasts, and  by  a  differential  count  will  be  found  always  to  out- 
number them  in  every  genuine  case  of  pernicious  anemia  at 
some  stage  of  the  disease.  This  blood  picture,  which  indicates 
a  megaloblastic  degeneration  of  the  bone  marrow,  due  in  all  proba- 
bility to  the  influence  of  some  unknown  but  specific  toxic  agency, 
is  associated  with  only  two  other  conditions,  namely,  nitrobenzol 
poisoning  and  some  cases  of  high-grade  anemia  due  to  Bothrio- 
cephalus  lotus  infection.  The  predominance  of  megaloblasts 
over  normoblasts  in  pernicious  anemia  is  well  illustrated  by  Table 
V,  which  shows  that  at  the  first  examination  the  former  type  of 
cells  outnumbered  the  latter  in  26  of  the  29  cases  here  collected. 
The  average  proportion  of  megaloblasts  to  normoblasts  in  this 
series  is  somewhat  more  than  2  to  1,  and  in  some  cases  the 
former  were  the  only  kind  of  erythroblast  discovered.  The 
total  number  of  erythroblasts  of  all  varieties  averaged  220  per 
c.mm.  of  blood,  ranging  from  as  low  as  3  to  as  high  as  924. 
Regarding  this  last  statement,  it  should  be  remembered  that  it 
is  not  the  actual  number  of  nucleated  erythrocytes,  but  their 
character,  which  is  all  important  in  the  diagnosis  of  this  disease. 
In  52  additional  cases  of  pernicious  anemia  a  predominance  of 
megaloblasts  was  found  in  50,  either  at  the  first  or  by  later  examin- 
ation, a  total  of  76  megaloblastic  bloods  in  the  81  cases  studied. 
Of  139  cases  reported  by  Cabot,  megaloblasts  predominated  in 
109  at  the  first  examination,  and  in  all  but  3  of  the  remaining  30 
cases  at  a  subsequent  period. 

1  hoc.  cit. 

2  In  Ehrlich's  "aplastic  anemia,"  a  fatal  type  with  profound  oligocythemia, 
leucopenia,  and  purpura,  the  marrow  so  utterly  fails  to  compensate  the  blood  loss 
that  erythroblasts  of  all  varieties  are  wanting.  Such  cases  are  obviously  not  typical- 
pernicious  anemia. 


PERNICIOUS  ANEMIA. 


283 


TABLE  V.— APPROXIMATE  NUMBER  OF  NUCLEATED  ERYTHRO 
CYTES  PER  C.MM.  IN  29  CASES  OF  PERNICIOUS  ANEMIA 
AT  THE  FIRST  EXAMINATION. 


Number. 

Total. 

Megaloblasts. 

Normoblasts. 

MlCROB  LASTS. 

I 

924 



693 

210 

21 

2 

840 

616 

140 

84 

3 

544 

512 

16 

l6 

4 

470 

320 

150 

O 

5 

368 

207 

46 

115 

6 

336 

240 

90 

6 

7 

328 

0 

328 

0 

8 

260 

20 

240 

0 

9 

256 

144 

80 

32 

10 

250 

180 

70 

*o 

11 

235 

175 

60 

0 

12 

224 

168 

56 

0 

13 

204 

148 

56 

0 

14 

200 

160 

40 

0 

15 

192 

180 

12 

0 

16 

160 

96 

64 

0 

17 

IOI 

80 

21 

0 

18 

100 

0 

TOO 

0 

19 

96 

73 

23 

0 

20 

67 

47 

I3 

21 

60 

40 

20 

0 

22 

48 

32 

10 

0 

23 

48 

37 

7 

4 

24 

32 

24 

8 

0 

25 

20 

20 

0 

0 

26 

15 

i5 

0 

0 

27 

10 

8 

0 

2 

28 

6 

6 

0 

0 

29 

3 

3 

0 

0 

Average:           220  -(- 

146  + 

64  + 

10 

Microblasts  are  rare  in  comparison  to  the  other  forms  of  mi-  ' 
cleated  erythrocytes;  in  some  cases  they  may  be  relatively  nu- 
merous, but  in  the  majority  they  are  absent.  They  were  noted 
in  but  9  of  the  29  cases  tabulated  above  (Table  V),  their  average 
number  for  the  series  being  10  to  the  c.mm.  In  the  differential 
count  of  nucleated  erythrocytes  microblasts  should  be  totaled 
with  normoblasts,  of  which  they  are  simply  degenerate  forms, 
more  or  less  stripped  of  their  protoplasm,  and  hence  irregular 
and  ragged  in  outline. 

In  addition  to  the  foregoing  types  of  erythroblasts,  cells  pos- 
sessing the  characteristics  of  both  the  normoblast  and  the  meg- 
aloblast  may  be  observed  in  many  instances.  These  atypical 
forms  and  their  clinical  significance  have  been  described  in  a 
previous  section.  (See  p.  192.)  In  certain  corpuscles,  both  of  the 
normoblastic  and  of  the  megaloblastic  types,  division  of  the  nu- 


284 


MSKASKS   OF   THE  BLOOD. 


cleus  into  several  parts  may  have  occurred,  and  in  rare  instances 
evidences  of  true  karyokinesis  may  be  seen.  Normoblasts  show- 
ing complete  or  partial  nuclear  extrusion  and  ^separation  of  the 
nucleus  into  a  clover-leaf  design  are  not  uncommon,  although 
pictures  of  this  sort  are  found  much  more  frequently  in  leukemia. 
In  many  cases  of  pernicious  anemia  one  cannot  but  be  struck 
with  the  fact  that  the  majority  of  these  atypical  forms  appear  as 
cells  with  a  megaloblastic  protoplasm  and  a  normoblastic  nucleus; 
they  are,  in  the  author's  experience,  much  more  numerous  in  this 
disease  than  cells  having  a  normoblastic  protoplasm  and  a  meg- 
aloblastic nucleus,  the  latter  being  more  common  in  leukemia. 


TABLE  VI.— QUALITATIVE  CHANGES   IN  THE  LEUCOCYTES  IN 
31  CASES  OF  PERNICIOUS  ANEMIA  AT  THE 
;  FIRST  EXAMINATION. 


Percentage  of  Different  Forms. 

No. 

1  ^EUCOCYTES 
PER  C.MM. 

Small 
Lympho- 
cytes. 

Large 
Lympho- 

Polynuclear 
Neutrophiles. 

EOSINOPHILES. 

Myelo- 
cytes. 

1 

13,000 

43-2 

2.8 

49.6 

2.8 

1.6 

2 

0,200 

7-7 

2.0 

86.2 

1.6 

2-5 

3 

7,000 

14.4 

1.6 

81.6 

2.0 

0.4 

4 

7,000 

13.6 

5-2 

77.6 

2.8 

0.8 

5 

6,400 

34-o 

4.0 

60.0 

1.0 

1.0  . 

6 

6,000 

1 1 .0 

2.0 

84.0 

1.0 

2.0 

7 

5,800 

14.0 

3-° 

73  -o 

0.0 

10.0 

8 

5;400 

22.1 

7-5 

67.4 

2.0 

1.0 

9 

5,000 

32.8 

3-6 

55-6 

5-2 

2.8 

10 

4,600 

56.5 

6.0 

34-5 

0.0 

3-° 

11 

4,100 

53-° 

6.4 

39-6 

0.0 

1.0 

12 

4,000 

30.0 

14-5 

52-4 

2.0 

I.I 

13 

4,000 

26.8 

15-5 

56.8 

0.9 

0.0 

14 

4,000 

23.0 

16.6 

58.2 

1.2 

1.0 

15 

4,000 

15.0 

5-° 

77-5 

°-5 

2.0 

16 

4,000 

34-o 

9.0 

45 -o 

8.0 

4.0 

17 

4,000 

16.3 

8.1 

72.6 

2.0 

1.0 

18 

3,100 

19.7 

23.0 

54-° 

1.0 

2-3 

19 

3,000 

10.8 

20.0 

60.0 

7.2 

2  O 

20 

2,500 

45 -o 

12.0 

40.0 

1.0 

2.0 

21 

2,300 

22.1 

16.1 

60.8 

0.0 

I.O 

22 

2,100 

32.1 

21.3 

40.7 

1.6 

4-3 

23 

2,080 

45 -o 

14.7 

38.3 

1.0 

1.0 

24 

2,000 

65.0 

20.0 

14. 1 

0.0 

0.9 

25 

2,000 

14-5 

14-5 

69-5 

1.0 

°-5 

26 

1,500 

25.0 

14.0 

61.0 

0.0 

0.0 

27 

1,100 

19. 1 

12. 1 

67.7 

°-3 

0.8 

28 

1,000 

17.0 

21.0 

'  58-o 

2.0 

2.0 

29 

1,000 

13.0 

11.0 

72.0 

1.0 

3-° 

3° 

1,000 

20.0 

9.0 

70.0 

0.5 

°-5 

3i 

500 

37-5 

18.5 

40.8 

2-3 

0.9 

Average:   3,925  -f 

26  + 

10  + 

58  + 

1  + 

1  + 

PERNICIOUS  ANEMIA. 


285 


Fluctuations  in  the  total  number  of  erythroblasts  occur  from 
time  to  time  during  the  progress  of  the  disease,  these  changes 
sometimes  taking  place  with  great  abruptness,  being  of  wide 
range  and  often  carrying  not  the  slightest  clinical  import.  A 
marked  increase  usually  but  not  invariably  precedes  and  accom- 
panies a  gain  in  the  number  of  erythrocytes  and  in  the  percentage 
of  hemoglobin;  and  a  similar  increase,  usually  associated  with 
extreme  diminution  in  the  erythrocyte  count,  is  commonly  met 
with  as  a  preagonal  sign. 

Marked  evidences  of  polychromatophilia  are  found  in  many  of 
the  erythrocytes,  both  of  the  nucleated  and  of  the  non-nucleated 
varieties.  Such  cells,  when  stained  with  Ehrlich's  triacid  mix- 
ture, instead  of  taking  the  normal  orange  color  of  the  solution, 
stain  some  bastard  tint,  such  as  slate  color,  dull  purple,  or  dirty 
gray.  Others  may  show  a  peculiar,  streaked  appearance,  and 
irregular,  pale,  unstained  areas,  while  others  are  scarcely  stained  at 
all,  the  greater  part  of  the  protoplasm  remaining  an  indefinite  shade 
of  dead  white.  Granular  degeneration  of  the  protoplasm  is  distinctly 
evidenced  in  some  of  the  cells,  this  process  being  betrayed  by  the 
appearance  through  the  stroma  of  granular  areas  showing  a  striking 
affinity  for  a  basic  stain,  such  as  methylene-blue.  These  basophilic 
granules,  which  have  already  been  described,  are  not  peculiar  to 
pernicious  anemia,  since  they  have  been  found  in  a  large-  number 
of  secondary  anemias  of  severe  type  due  to  various  causes.  (See 
p.  194.) 

The  same  remarks  apply  to  the  presence  of  erythrocytes  con- 
taining the  "ring  bodies"  of  Cabot.  This  author1  reports  having 
found  them  in  9  of  14  cases  of  pernicious  anemia  examined  during 
the  active  stages,  but  he  failed  to  detect  them  in  4  cases  in  the 
stages  of  remission. 

TABLE  VII.— NUMBER  OF  LEUCOCYTES  IN  81  CASES  OF 
PERNICIOUS  ANEMIA 


Leucocytes  Number  of 

per  c.mm.  Cases. 

From  10,000-15,000   3 

"      5,000-10,000  25 

Below  5,000  53 


Average,       4527  per  c.mm. 
Maximum,  15,000  "  " 
Minimum,      500  "  " 

Leucopenia  may  be  counted  on  in  considerably 
Leucocytes,  more  than  one-half  of  all  cases  of  pernicious 
anemia,  a  fact  which  stands  in  direct  contrast  to 
the  anemias  of  secondary  type,  in  which  an  increase  in  the  number 

1  Boston  Med.  and  Surg.  Jour.,  1904,  vol.  cl,  p.  321. 


286 


DISEASES  OF  THE  BLOOD. 


of  leucocytes  is  more  common.  In  an  occasional  case,  especially 
in  one  in  which  the  other  blood  changes  are  inconspicuous,  the 
number  of  leucocytes  is  found  to  be  normal;  and,  rarely,  a  mod- 
erate leucocytosis,  attributable  to  some  complication,  exists.  In 
the  average  case,  however,  these  cells  are  distinctly  below  the  nor- 
mal standard,  and  the  degree  of  leucopenia  is  sometimes  extreme, 
the  number  of  cells  occasionally  falling  to  below  iooo  to  the 
c.mm.;  in  rare  instances  they  may  apparently  be  entirely  absent, 
none  being  found  after  prolonged  search  through  both  the  count- 
ing chamber  and  the  stained  film.  In  the  81  cases  collected  in 
Table  VII  the  number  of  leucocytes  averaged  about  the  mean  low 
normal  count  (4527  being  the  exact  figure),  and  ranged,  in  the 
individual  case,  from  500  to  as  high  as  15,000  to  the  c.mm.  It  is 
interesting  to  note,  in  connection  with  the  preceding  remarks,  that 
leucopenia  was  found  in  53  or  65.4  per  cent,  of  these  cases. 

The  leucocyte  count,  except  in  the  event  of  complications, 
roughly  parallels  that  of  the  erythrocytes,  falling  coincidentally 
with  the  oligocythemia  and  rising  again  as  the  erythrocytes  in- 
crease. (See  chart,  p.  279.)  An  exception  to  this  general  rule 
is  found  in  the  terminal  leucocytosis  which  not  uncommonly 
develops  just  before  the  death  of  the  patient. 

Relative  lymphocytosis  is  a  common,  but  not  a  constant,  find- 
ing in  the  differential  count  of  the  stained  film.  It  seems  to  be 
more  frequently  associated  with  low  than  with  high  counts, 
although  no  hard-and-fast  rule  can  be  laid  down  regarding  this 
point.  In  extremely  leucopenic  blood  a  noteworthy  finding  is 
the  abnormally  high  percentage  of  large  mononuclear  non-gran- 
ular cells,  a  change  which  does  not  ordinarily  take  place  in  con- 
nection with  leucocyte  counts  approaching  the  normal  average. 
The  combined  percentage  of  both  large  and  small  forms  of 
lymphocytes  in  Table  VI  averaged  37.8,  individual  counts  vary- 
ing from  9.7  to  85  per  cent.  The  writer  has  noted  the 
frequent  occurrence  of  small  lymphocytes  containing  coarse 
basic  granules.  Such  cells  appear  to  be  especially  common  in 
this  form  of  anemia.  Preagonal  rises  in  the  leucocyte  count 
are  sometimes  lymphocytic  in  character,  resembling  the  blood 
changes  seen  in  lymphatic  leukemia,  and  sometimes  purely  poly- 
nuclear  in  type.  The  relative  percentage  of  poly  nuclear  neutro- 
philes  averages  low  (58.6  per  cent',  in  the  above  series),  but  iso- 
lated counts  show  a  considerable  range;  their  relative  proportion 
to  the  other  forms  of  leucocytes  is  largely  determined  by  the 
fluctuations  in  the  percentage  of  lymphocytes.  The  eosinophils 
are  almost  invariably  decreased,  and  not  infrequently  they  are 
wholly  wanting,  a  circumstance  which  was  made  note  of  in  more 


PERNICIOUS  ANEMIA. 


287 


than  18  per  cent,  of  the  cases  in  the  present  series,  in  which  the 
average  percentage  of  these  cells  was  1.68.  In  an  occasional 
case  their  percentage  is  above  normal,  as  in  cases  9,  16,  and  19 
in  Table  VI. 

In  no  other  disease  save  the  myelogenous  form  of  leukemia 
are  myelocytes  so  constantly  found,  but  almost  always  in  relatively 
small  percentages.  In  the  cases  under  consideration  these  cells 
were  absent  in  only  two  instances,  the  average  figure  for  the  31 
cases  being  1.82  per  cent.  In  a  single  case  (number  7)  the  re- 
markably high  estimate  (for  this  disease)  of  10  per  cent,  of  myelo- 
cytes was  made,  for  in  the  other  cases  in  which  myelocytes  oc- 
curred their  percentage  ranged  from  0.4  to  4.3. 

In  the  stained  specimen  it  is  common  to  find  that  the  leuco- 
cytes, particularly  the  polynuclear  neutrophiles  and  the  myelo- 
cytes, are  of  smaller  size  and  more  deeply  stained  than  they  ap- 
pear in  normal  blood.  This  peculiarity  seems  to  be  more  con- 
stant and  more  striking  in  pernicious  anemia  than  in  any  other 
disease. 

The  number  of  blood  plaques  is  exceedingly 
Blood       variable,  so  that  it  is  impossible  to  make  definite 
Plaques.      statements  regarding  either  the  increase  or  the 
decrease  of  these  bodies.    In  some  cases  they 
apparently  are  greatly  increased,  as  evidenced  by  the  groups  of 
agglutinated  masses  of  these  cells  which  are  sometimes  seen 
(von  Limbeck1),  but  in  other  cases  it  is  evident  that  their  number 
is  appreciably  diminished  (Hay em2).    Van  Emden3  supports  the 
latter  view.    In  one  case  this  observer  estimated  their  number  at 
between  32,000  and  64,000  per  c.mm. 

In  a  typical  case  of  pernicious  anemia  the 
Diagnosis,    blood  picture  upon  which  the  diagnosis  rests  is 
as  follows: 

Hemoglobin.  Marked  absolute  decrease,  but  of  relatively  higher 
percentage  than  that  of  the  erythrocytes,  this 
giving  rise  to  a  high  color  index.    Striking  de- 

Erythrocytes.      crease,  commonly  to  1,000,000  or  less  per  c.mm. 

Counts  of  about  500,000  are  not  uncommon 
during  the  later  stages  of  the  disease.  Erythro- 
blasts  constant,  cells  of  the  megaloblastic  type 
predominating. 

Megalocytes  and  microcytes,  the  former  prevailing. 
Poikilocytes,  usually  numerous  and  conspicuous. 
Polychromatophilia. 

1  Loc.  cit.  2  "Lemons  sur  les  Maladies  du  Sang,"  Paris,  igco. 

3  "Bijd.  t.  d.  ken.  v.  h.  bloed,"  Leyden,  1896. 


288 


DISKASKS   OF   THE  BLOOD. 


Basophilic  stroma  degeneration  striking  in  severe 
cases. 

Leuc  ocytes.         Usually  decreased;  decided  leucopenia  common. 

Relative  lymphocytosis  in  the  majority  of  cases. 
Small  numbers  of  myelocytes  almost  invariably 
present. 

Eosinophiles  few,  sometimes  absent. 
Plaques.  Variable. 

Usually  the  diagnosis  of  pernicious  anemia  presents  no  difficul- 
ties, and  may  be  made  by  the  examination  of  the  blood  alone, 
the  association  of  marked  oligocythemia,  a  high  color  index,  leu- 
copenia, and  erythroblasts,  chiefly  of  the  megaloblastic  variety, 
constituting  a  typical  group  of  blood  changes  the  significance  of 
which  is  unmistakable. 

It  should  be  borne  in  mind,  however,  that  these  changes  are 
not  always  present  in  every  case  when  the  patient  first  comes 
under  observation,  so  that  repeated  and  careful  examinations  of 
the  blood  are  sometimes  necessary  before  a  diagnosis  is  possible. 
Of  the  above-named  changes,  the  most  important,  from  a  clinical 
viewpoint,  is  the  prevalence  of  nucleated  erythrocytes  conforming 
to  the  megaloblastic  type.  With  the  two  exceptions  already  noted 
(bothriocephalus  anemia  and  nitrobenzol  poisoning)  this  "mega- 
loblastic blood  picture "  is  seen  only  in  pernicious  anemia,  and, 
what  is  more  important,  it  occurs  in  every  true  case  of  this  dis- 
ease sooner  or  later  during  its  course.  Inability  to  detect  this 
important  characteristic  should  be  regarded  rather  as  a  reflection 
upon  the  thoroughness  of  the  examiner's  technic  than  as  a  con- 
tradiction of  the  truth  of  this  statement.  Erythroblasts  are  not 
always  numerous  in  pernicious  anemia,  and  painstaking  and  pro- 
longed study  of  several  stained  films  may  be  necessary  before 
this  important  feature  is  distinguishable. 

In  those  cases  of  doubtful  nature  in  which  the  typical  blood 
changes  are  not  at  once  evident  a  tentative  diagnosis  may  be 
made  by  taking  into  careful  consideration  certain  other  physical 
signs  and  symptoms  which  the  patient  presents.  In  such  in- 
stances attention  should  be  directed  to  such  suspicious  points  in 
the  clinical  history  as  the  existence  of  a  severe  anemia  arising 
either  idiopathically  or  without  adequate  cause,  and  pursuing  a 
progressively  unfavorable  course,  uninfluenced  permanently  by 
treatment;  the  presence  of  a  light  lemon-yellow  tint  of  the  skin, 
of  retinal  hemorrhages,  of  a  peculiarly  soft,  smooth,  flabby  condi- 
tion of  the  skin,  and  sometimes  of  moderate  febrile  paroxysms 
and  gastric  disturbances;  and  the  remarkable  preservation  of  the 
patient's  general  nutrition  and  body- weight  in  comparison  with 
the  severity  of  the  illness. 


l'KRNICIOUS  ANKMIA. 


289 


The  severe  secondary  anemias  due  to  hemorrhage,  to  advanced 
syphilis,  and  to  malignant  disease,  especially  of  the  stomach, 
sometimes  give  rise  to  clinical  symptoms  which  so  exactly  simu- 
late pernicious  anemia  that  the  diagnosis  must  rest  upon  the  re- 
sult of  the  blood  findings,  which  are  usually  well  enough  marked 
to  differentiate  the  conditions.  It  is  true  that  in  these  conditions 
ample  proof  of  sufficient  etiological  factors  for  the  production  of 
the  anemia  is  generally  at  hand,  and  this  fact  should  have  im- 
portant bearing  in  ruling  out  anemia  of  the  pernicious  type,  but 
it  is  also  equally  true  that  in  malignant  disease  it  is  sometimes 
impossible  to  demonstrate  the  lesion,  and  that  in  syphilis  the 
clinical  history  may  be  obscure,  so  that  the  blood  examination 
must,  after  all,  often  be  depended  upon  for  an  accurate  diag- 
nosis. In  secondary  anemia  from  the  above  causes  the  oligo- 
cythemia is  seldom  so  excessive  as  it  is  in  pernicious  anemia,  the 
erythrocytes  rarely  falling  as  low  as  1,000,000  per  c.mm.;  the 
oligochromemia  is  likely  to  be  relatively  greater  than  the  oligo- 
cythemia, so  that  a  lower  color  index  results;  leucocytosis  is 
not  uncommon;  and  while  deformities  of  shape  and  size  and 
nucleation  of  the  erythrocytes  are  frequently  present,  in  some 
instances  to  as  great  an  extent  as  in  pernicious  anemia,  megalo- 
cytes  do  not  predominate,  nor  do  megaloblasts  ever  outnumber 
normoblasts. 

From  chlorosis,  which  sometimes  possesses  many  clinical  mani- 
festations in  common  with  pernicious  anemia,  the  diagnosis  may 
usually  be  readily  made  by  the  blood  examination,  which  shows 
decided  differences  between  the  two  diseases.  In  a  typical  case 
of  chlorosis  the  deterioration  in  the  quality  of  the  blood  affects 
chiefly  the  hemoglobin  content  of  the  erythrocytes  and  not  the 
cells  themselves.  Hence  it  is  common  to  find  in  this  disease 
extreme  oligochromemia  out  of  all  comparison  with  the  more 
moderate  oligocythemia,  and  consequently  a  low  color  index — 
just  the  reverse  of  the  condition  found  in  pernicious  anemia. 
Deformities  in  the  shape  and  size  of  the  erythrocytes  are  not 
uncommon  in  chlorosis,  but  they  are  not  likely  to  be  con- 
spicuous ;  the  prevalent  change  affecting  their  shape  is  micro- 
cytosis  of  a  moderate  grade,  so  that  a  general  decrease  in  the 
diameter  of  these  cells  is  commonly  observed.  The  most  im- 
portant information  derived  from  the  blood  is,  however,  of  a 
negative  character,  consisting  in  the  fact  that  nucleated  erythro- 
cytes, should  they  be  present,  are  chiefly  normoblasts.  While 
it  is  true  that  an  occasional  megaloblast  may  be  encountered  in 
rare  instances,  no  chlorotic  blood  has  ever  been  known  to  show 
a  predominance  of  this  type  of  cells.  The  behavior  of  the  leuco- 
z9 


290 


DISKASKS   OK   THE  BLOOD. 


cytes  in  chlorosis  is  of  no  aid  in  the  differentiation  of  this  condi- 
tion from  pernicious  anemia,  for  in  both  diseases  the  count  is 
usually  low  and  relative  lymphocytosis  common;  in  the  former, 
however,  the  pronounced  leucopenia  of  the  latter  condition  is  not 
often  found.  Myelocytes,  while  they  may  occur  in  both  diseases, 
are  much  less  common  in  chlorosis. 

In  bothriocephalus  anemia  the  expulsion  of  the  parasite  by  the 
administration  of  an  appropriate  vermifuge  is  soon  followed  by  a 
radical  change  in  the  blood  picture  and  other  symptoms,  the  meg- 
aloblasts  disappearing,  the  hemoglobin  and  erythrocytes  quickly 
rising  to  the  normal  standard,  and  the  patient's  health  becoming 
entirely  restored.  The  history  of  a  patient  suffering  from  anemia 
due  to  nitrobenzol  poisoning  is  sufficiently  characteristic  to  exclude 
true  pernicious  anemia.  The  differential  diagnosis  between  this 
disease  and  splenic  anemia  is  considered  in  another  place.  (See 

p-  295O  '  =  y 

Several  reputed  instances  of  the  conversion  of  pernicious 
anemia  into  leukemia  have  been  reported  by  Leube  and  Fleischer,1 
Waldstein,2  and  Litten.3  Some  such  cases  probably  belong, 
as.  also  do  many  cases  of  acute  leukemia,  to  Leube 's  symptom- 
complex,  "leukanemia"  4 — high-grade  anemia  plus  either  myelemia 
or  lymphocytosis,  with  fever,  hemorrhage,  stomatitis,  and  hyper- 
plasia of  the  spleen  and  lymphatics.  That  pernicious  anemia  is 
ever  converted  into  leukemia  is  questionable,  and  it  seems  reason- 
able to  regard  such  a  change  as  apparent  rather  than  real.  For 
example,  in  a  case  of  leukemia,  transient  disappearance  of  the 
myelemia,  with  persistence  of  the  anemia,  such  as  may  occur  either 
spontaneously  or  from  treatment,  gives  a  blood  picture  not 
unlike  that  of  true  pernicious  anemia,  and  a  case  of  this  sort  may 
appear  to  become  converted  into  leukemia,  as  the  temporarily 
suppressed  leukemic  blood  changes  redevelop  in  course  of  time. 
A  marked  leucocytosis  engrafted  upon  pernicious  anemia  may 
also  be  mistaken  for  the  transformation  of  this  disease  into  leu- 
kemia, but  it  is  obvious  that  this  counterfeit  can  be  detected  by 
a  differential  count  of  the  leucocytes. 

1  Virchow's  Arch.,  1881,  vol.  lxxxiii,  p.  124.  2  Ibid.,  1883,  vol.  xci,  p.  12. 

3  Berlin,  klin.  Wochenschr.,  1877,  vol.  xiv,  p.  256. 

*  Munch,  med.  Wochenschr.,  1900,  vol.  xlvii,  p.  1121.  See  also  Arneth,  Deutsch. 
Arch.  f.  klin.  Med.,  1901,  vol.  lxix,  p.  331;  Luce,  ibid.,  1903,  vol.  Ixxvii,  p.  215; 
F.  B.  Weber,  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  1416;  Kormoczi,  Deutsch.  med. 
"Wochenschr.,  1899,  vol.  xxv,  pp.  238  and  775;  Hitschman,  Zeitschr.  f.  Heilk., 
1903,  vol.  xxiv,  p.  190. 


SIM.KNIC  ANKMIA. 


291 


III.    SPLENIC  ANEMIA. 

There  is  nothing  distinctive  about  the  appear- 
Appearance  ance  of  the  drop  of  freshly  drawn  blood,  the 
of  the       color  and  density  of  which  vary  with  the  inten- 
Fresh  Blood,  sity  of  the  anemia  present.    The  author  has 
notes  of  a  case  of  splenic  anemia  in  which  it  was 
remarked  that,  from  its  color  and  general  appearance,  the  blood 
drop  resembled  precisely  that  obtained  from  a  typical  case  of 
high-grade  pernicious  anemia;  in  a  second  case  the  color  and 
opacity  were  but  slightly  below  normal. 

No  reliable  observations  have  thus  far  been  made  regarding 
such  minor  points  as  the  rate  of  coagulation,  the  specific  gravity, 
and  the  reaction  of  the  blood  in  this  form  of  anemia. 

Decided,  often  extreme,  anemia  is  the  general 
Hemoglobin  rule  in  this  disease.    In  the  early  stages  the 
and         hemoglobin  loss  is  relatively  excessive  as  com- 
Erythrocytes.  pared  to  the  decrease  in  erythrocytes,  so  that 
the  color  index  is  consequently  low — usually  ap- 
proximating the  figures  found  in  many  cases  of  high-grade  sec- 
ondary anemia,  but  not  averaging  so  low  as  in  chlorosis.    As  the 
disease  increases  in  severity,  however,  the  color  index  tends  to 
rise,  as  in  pernicious  anemia,  this  change  being  illustrated  by  the 
counts  tabulated  below. 

In  a  series  of  15  cases  reported  by  Osier1  the  following  re- 
sults were  obtained:  the  hemoglobin  in  13  cases  averaged  47 
per  cent.,  the  lowest  estimate  being  23  and  the  highest  60  per 
cent.;  42  erythrocyte  counts  averaged  3,336,357  per  c.mm.,  with 
extremes  of  2,000,000  and  5,200,000.  These  figures  are  very 
closely  approximated  by  the  averages  of  35  cases  collected  by 
Lichty2:  hemoglobin,  47  per  cent.;  erythrocytes,  3,293,000;  and 
leucocytes,  5594.  Similar  changes  were  found  in  series  of  cases 
reported  by  Rolleston 3  and  by  Frederick  Taylor.4 

In  a  case  of  splenic  anemia  in  Professor  Hare's  ward  at  the 
Jefferson  Hospital  the  writer  found  the  following  changes  in  five 
consecutive  counts: 


Erythrocytes 

Date.                         Hemoglobin.  Color  Index.         per  c.mm. 

March    7,  1898  45  per  cent.  0.82  2,750,000 

March  14,  1898  40    "     "  0.73  2,725,000 

March  22,  1898  43    "     "  0.76  2,812,000 

March  29,  1898  45    "     "  0.69  3,275,000 

April    11,  1898  40    "     "  1. 00  2,000,000 


1  Amer.  Jour.  Med.  Sci.,  1900,  vol.  cxix,  p.  54;  ibid.,  1902,  vol.  cxxiv,  p.  781. 

2  Jour.  Amer.  Med.  Assoc.,  1904,  vol.  xlii,  p.  528. 

3  "Splenic  Anemia,"  London,  1902.  ■  . 

4  Lancet,  1904,  vol.  i,  pp.  1477,  T554>  and  1636. 


292 


MSKASKS   OK   Til  K  BLOOD. 


Deformities  affecting  the  size  of  the  erythrocytes,  sometimes 
tending  toward  striking  megalocytosis,  may  be  met  with  in  cases 
characterized  by  great  oligocythemia,  such  an  alteration  being  also 
associated  with  a  greater  or  less  degree  of  poikilocytosis,  and  with 
signs  of  stroma  degeneration.  Nucleated  erythrocytes,  although 
they  occur  infrequently,  may  be  present  in  enormous  numbers 
in  severe  cases,  creating  a  blood  picture  which  is  distinguishable 
from  that  of  true  pernicious  anemia  only  by  the  fact  that  normo- 
blasts predominate.  Thus,  in  one  of  McCrae's  counts  in  a  case 
of  Osier's,  in  which  the  hemoglobin  was  reduced  to  20  and  the 
erythrocytes  to  27.6  per  cent.,  no  fewer  than  75  erythroblasts 
(of  which  21  were  normoblasts,  19  megaloblasts,  and  35  "inter- 
mediate" forms)  were  seen  while  counting  400  leucocytes.  In 
the  case  above  summarized  the  average  number  of  erythroblasts 
per  1000  leucocytes  was  estimated  as  67  (the  maximum  and 
minimum  being  128  and  9,  respectively)  for  the  five  examinations, 
41  of  these  cells  being  normoblasts  and  26  megaloblasts.  The 
presence  of  nucleated  erythrocytes  in  such  large  numbers  as  were 
found  in  these  two  instances  must,  however,  be  regarded  as  most 
exceptional.  Polychromatophilia  of  many  of  the  erythrocytes 
may  be  a  striking  feature  in  advanced  cases,  but  in  those  of  a 
milder  grade  the  phenomenon  is  absent.  Absence  of  basophilic 
granular  degeneration  of  the  cells  has  been  noted  by  Cohn.1 

The  transition  of  splenic  anemia  into  lymphatic  leukemia  has 
been  recorded  twice  in  medical  literature,  according  to  Zypkin,2 
who  himself  encountered  such  a  change. 

Leucopenia,  sometimes  pronounced,  is  the 
Leucocytes,  characteristic  finding,  counts  of  from  2000  to 
4000  cells  to  the  c.mm.  being  common;  as  in 
pernicious  anemia,  the  lowest  leucocyte  counts  are  generally 
associated  with  those  cases  in  which  the  anemia  is  most  intense. 
In  the  adult  leucocytosis  occurs  only  as  the  effect  of  some  compli- 
cation, and  therefore  is  but  occasionally  encountered.  In  Osier's 
series,  above  referred  to,  the  number  of  leucocytes,  determined  in 
14  cases,  averaged  4520  per  c.mm.,  ranging  from  2000  to  12,497, 
the  latter  estimate  being  the  only  one  exceeding  10,000;  in  9  of  the 
cases  the  count  fell  below  5000.  In  the  writer's  case  the  five 
counts  averaged  2400,  varying  from  1000  to  4000.  In  children, 
also,  leucopenia  is  the  rule,  in  spite  of  a  child's  tendency  to 
develop  leucocytosis  upon  the  slightest  provocation.  (See  p. 
347-) 

1  Munch,  med.  Wochenschr.,  1900,  vol.  xlvii,  p.  618. 

2  Wien.  klin.  Wochenschr.,  1903,  vol.  xvi,  p.  577. 


SPLENIC  ANEMIA. 


293 


No  constant  differential  changes  have  been  observed,  but  rela- 
tive lymphocytosis  is  not  infrequent,  sometimes  involving  chiefly 
the  large,  and  sometimes  the  small,  forms  of  these  cells.  The  pro- 
portion of  both  combined  may  be  as  high  as  50  or  60  per  cent., 
an  increase  of  this  kind  bringing  about  a  consequent  fall  in  the 
relative  percentage  of  polynuclear  neutrophiles.  Small  numbers 
of  myelocytes,  rarely  in  excess  of  a  fraction  of  one  per  cent.,  are 
to  be  expected  in  cases  with  decided  oligocythemia.  The  eosin- 
ophiles  remain  at  about  the  normal  standard.  Typical  coarsely 
granular  mast  cells  are  sometimes  found  in  relatively  large  numbers 
— as  high  as  5  or  6  per  cent,  of  all  forms  of  leucocytes. 

No  special  observations  concerning  the  behavior  of  the  blood 
plaques  in  this  disease  have  been  recorded  up  to  the  present  time. 
It  is  evident,  however,  that  they  are  not  notably  increased  in 
number. 

To  recapitulate,  the  blood  changes  which  have 
Diagnosis,    been  most  frequently  found  in  splenic  anemia 
may  be  tabulated  as  follows: 

Hemoglobin.      Marked  diminution;  color  index  variable. 

Erythrocytes.  Usually  reduced  moderately,  sometimes  exces- 
sively. Counts  between  3,000,000  and  4,000,000 
cells  per  c.mm.  are  most  common. 
Deformities  of  shape,  especially  megalocytosis, 
and  poikilocytosis  common  in  advanced  cases. 
Erythroblasts  rare,  except  in  cases  with  decided 
oligocythemia.  Normoblasts  invariably  predom- 
inate. 

Polychromatophilia  in  severe  cases. 
Leucocytes.        Leucopenia  the  general  rule. 

Relative  lymphocytosis  common. 

Small  numbers  of  myelocytes  in  advanced  cases. 

Relatively  large  percentages  of  mast  cells  not 

uncommon^ 

Eosinophiles  normal. 
Plaques.  Not  increased. 

Many  writers  still  hesitate  to  assign  to  splenic  anemia  the  role 
of  a  definite  clinical  entity,  choosing  to  regard  the  condition 
either  as  a  splenic  form  of  Hodgkin's  disease  or  as  high-grade 
secondary  anemia  with  marked  splenic  hyperplasia.  But  of  late 
the  majority  of  observers  lean  toward  at  least  a  tentative  recognition 
of  the  condition  as  a  distinct  although  an  obscure  disease.1  Osier/ 


1  For  a  critical  resume  of  the  literature  on  splenic  anemia,  Sippy's  article  in 
the  American  Journal  of  the  Medical  Sciences,  1899,  vol.  cxviii,  p.  570,  should  be 
consulted.  2  Loc.  cit. 


294 


DISEASES  OF  THE  BLOOD. 


well  expresses  the  consensus  of  opinion  when  he  remarks  that 
''provisionally,  until  we  have  further  knowledge,  it  is  useful  to 
group  together  .  .  .  cases  of  idiopathic  enlargement  of  the  spleen 
with  anemia  without  lymphatic  involvement,  and  to  label  the 
condition  splenic  anemia."  Banti's  disease,  or  the  terminal  stage 
of  splenic  anemia,  is  characterized  by  hypertrophic  liver  cirrhosis 
with  jaundice  and  by  ascites. 

It  is  quite  obvious,  from  a  glance  at  the  above  synopsis  of  the 
blood  condition,  that  splenic  anemia  presents  no  characteristic 
blood  picture  by  which  the  diagnosis  can  be  made,  so  that  in 
order  to  differentiate  it  from  a  number  of  other  diseases  which  it 
more  or  less  closely  simulates,  careful  study  of  other  clinical 
features  is  essential. 

The  onset  of  splenic  anemia  is  gradual  and  insidious,  its  course 
is  prolonged  often  for  a  number  of  years,  and  its  termination  is 
ultimately  fatal.  The  principal  clinical  features  are  the  leuco- 
penic  anemia,  the  great  splenic  tumor,  and  the  absence  of  en- 
largement of  the  superficial  lymphatics.  In  some  instances  the 
anemia  develops  in  advance  of  the  splenic  tumor,  but  it  is  more 
often  the  case  that  the  enlargement  of  the  spleen  is  the  earliest 
demonstrable  lesion.  The  anemia  is  responsible  for  such  symp- 
toms as  dyspnea,  vertigo,  cardiac  palpitation,  loss  of  strength 
and  appetite,  and  the  occurrence  of  unexplained,  irregular  periods 
of  fever;  and  for  such  signs  as  hemic  heart  murmurs,  pallor, 
lemon-yellow  discoloration  of  the  skin  and  mucous  membranes, 
and  sometimes  pigmentation  of  the  skin.  The  enlarged  spleen 
may  extend  as  far  down  as  the  umbilicus,  and  sometimes  far  be- 
low this  point,  even  to  the  iliac  crests;  the  surface  of  the  organ 
is  smooth  and  free  from  nodules,  its  consistence  is  firm,  and  its 
shape  is  unaltered.  It  may  give  rise  to  no  symptoms,  but  occa- 
sionally it  is  the  cause  of  great  pain  and  of  hematemesis,  the  latter 
being  due  to  simple  mechanical  congestion.  Epistaxis,  purpura, 
and  hematuria  have  also  been  observed.  Ascites  sometimes  de- 
velops, as  the  result  either  of  the  splenic  enlargement  or  of  the 
anemia.  Enlargement  of  the  liver,  usually  associated  with  de- 
cided icterus,  occurs  as  a  terminal  symptom,  and  such  gastro- 
intestinal disturbances  as  anorexia,  nausea,  vomiting,  and  both 
constipation  and  diarrhea  are  extremely  common.  Splenic  anemia 
may  prove  fatal  within  six  months  after  the  onset  of  the  initial 
symptoms,  or  it  may  drag  along  for  as  many  years,  but  as  a 
general  rule  its  duration  does  not  exceed  two  or  three  years. 
In  one  of  Osier's  cases  the  condition  probably  lasted  for  at  least 
twelve  years,  and  in  a  case  recently  treated  in  the  Jefferson 
Hospital  the  splenic  tumor  and  the  anemia  existed  for  six  years, 


SPLENIC  ANEMIA. 


295 


if  not  longer.  As  in  pernicious  anemia,  periods  of  remission  dur- 
ing which  the  leading  symptoms  disappear  and  the  quality  of  the 
blood  improves  are  commonly  observed  in  this  condition. 

The  myelogenous  form  oj  leukemia,  pernicious  anemia ,  and 
Hodgkin's  disease  with  splenic  enlargement  all  present  clinical 
features  counterfeiting  more  or  less  faithfully  splenic  anemia,  but 
the  differential  diagnosis  between  these  conditions  does  not  in- 
volve any  great  difficulty.  The  result  of  the  blood  examination 
gives  the  clue  to  the  two  diseases  first  named,  the  myelocytic 
type  of  blood  in  leukemia  and  the  predominance  of  megaloblasts 
in  pernicious  anemia  being  sufficient  to  fix  the  identity  of  these 
conditions.  In  Hodgkin's  disease  with  enlargement  of  the  spleen 
there  is  more  or  less  marked  enlargement  of  the  superficial  lym- 
phatic glands,  and  the  splenic  tumor  rarely  attains  the  size  to 
which  it  grows  in  splenic  anemia;  the  blood  picture  of  the  two 
conditions,  it  must  be  recalled,  may  be  identical. 

Enlargements  of  the  spleen  due  to  such  factors  as  chrome  ma- 
larial injection,  amyloid  disease,  malignant  growths,  echinococcus 
cysts,  and  hepatic  cirrhosis  also  occasionally  require  differentiation 
from  splenic  anemia.  A  history  of  previous  attacks  of  malarial 
fever  and  the  detection  of  the  specific  parasite  or  of  pigment  an 
the  blood  will  serve  to  distinguish  tumors  of  the  spleen  of  malarial 
nature.  In  amyloid  disease  a  history  of  long-standing  suppura- 
tion, of  tuberculosis,  or  of  syphilis,  and  the  presence  of  signs  in- 
dicating amyloid  involvement  of  other  organs,  notably  the  liver, 
kidneys,  and  intestines,  are  the  chief  differentiating  features.  In 
malignant  disease  of  the  spleen  the  tumor  is  uneven,  irregular, 
and  nodular,  evidences  elsewhere  of  malignant  lesions  generally 
exist,  and  a  well-defined  leucocytosis  is  common.  Echino- 
coccus disease  of  the  spleen  pursues  a  protracted  course  unac- 
companied by  signs  of  anemia,  but  generally  shows  decided 
eosinophilia,  and,  unless  secondary  infection  takes  place,  is  unas- 
sociated  with  rises  in  temperature;  fluctuation  of  the  tumor  can 
frequently  be  detected,  and  hooklets  can  be  recognized  in  the 
fluid  obtained  from  the  organ  by  aspiration.  In  splenic  enlarge- 
ments associated  with  the  different  varieties  of  hepatic  cirrho- 
sis, the  previous  history  and  the  cachexia  of  the  patient,  the 
relatively  moderate  size  of  the  tumor,  the  signs  of  portal  con- 
gestion, the  condition  of  the  liver,  and  the  course  of  the  disease 
should  be  taken  into  account. 


296 


DISEASES  OF  THE  BLOOD. 


IV.    SECONDARY  ANEMIA. 

An  approximate  idea  of  the  intensity  of  the 
Appearance  anemia  may  usually  be  formed  by  noting  the 
or  the       gross  appearance  of  the  fresh  blood  drop,  but  it 
Fresh  Blood,  must  be  remembered  that  it  is  only  when  the 
process  has  reached  a  comparatively  high  grade 
of  development  that  the  fact  is  betrayed  by  any  marked  devia- 
tion from  normal  in  the  color  and  density  of  the  blood.    In  the 
average  case  of  well-marked  secondary  anemia  the  color  of  the 
•drop  is  but  slightly  paler  than  normal,  if,  indeed,  it  is  visibly  al- 
tered; but  if  the  anemia  is  of  decided  severity,  it  may  resemble  a 
thin,  serum-colored  liquid  streaked  with  crimson,  similar  to  the 
watery  blood  drop  of  typical  pernicious  anemia.    In  such  cases 
microscopical  examination  of  the  fresh  film  shows  that  there  is 
little  or  no  tendency  toward  rouleaux  formation. 

In  general  terms  it  may  be  stated  that  the 
Coagulation,  rapidity  of  coagulation  bears  a  direct  relation 
to  the  grade  of  the  anemia,  since  it  has  been 
determined  that  the  greater  the  oligochromemia  and  oligocy- 
themia, the  more  rapid  the  process  of  clotting.  In  secondary 
anemias  with  erythrocyte  counts  under  1,000,000  Lenoble  1  found 
that  coagulation  was,  as  a  rule,  at  least  twice  as  rapid  as  normal. 

The  specific  gravity  of  the  whole  blood  is  re- 
Specific      duced,  a  change  which  is  dependent  chiefly  upon 
Gravity.     the  loss  of  hemoglobin.    Sufficient  reference  has 
already  been  made  to  this  subject  in  a  previous 
section.    (See  p.  132.) 

The  majority  of  authors  maintain  that  the  al- 
Alkalinity.  kalinity  of  the  blood  is  decreased  in  relation  to 
the  degree  of  the  anemia,  and  a  large  number  of 
experiments  in  anemias  due  to  various  factors  apparently  justify 
this  general  belief.  But  several  careful  investigators,  notable 
among  whom  is  Lowy,2  have  contradicted  these  reports,  having 
found  the  alkalinity  normal  or  even  above  normal  in  numerous 
cases.  ^  The  author  quoted,  for  example,  calculated  the  alkalinity 
in  various  cases  of  secondary  anemia  at  from  360  to  675  mgm. 
NaOH,  as  compared  with  his  normal  standard,  447  to  508  mgm. 

Taking  the  ordinarily  well-developed  case  of 
Hemoglobin  secondary  anemia  as  an  example,  it  is  found  that 
and         the  hemoglobin  percentage  and  number  of  ery- 
Erythrocytes.  throcytes  are  both  decidedly,  though  not  strikingly, 
diminished.    As  the  former  usually  shows  a  dis- 

1  hoc.  cit.  2  Centralbl.  f.  d.  med.  Wissensch.,  1894,  vol.  xxxii,  p.  785. 


SECONDARY  ANEMIA. 


297 


proportionately  greater  loss  than  the  latter,  subnormal  color  in- 
dices are  the  rule,  ranging,  say,  from  about  0.75  to  0.85.  In 
anemias  of  severer  type,  such  as  those  due  to  gastric  cancer  and 
to  enteric  fever,  the  losses  frequently  are  much  more  exaggerated, 
and,  in  so  far  as  the  purely  quantitative  changes  in  the  erythro- 
cytes and  their  hemoglobin  equivalent  are  concerned,  the  blood- 
picture  of  true  pernicious  anemia  may  be  counterfeited.  In  the 
anemias  of  syphilis,  of  tuberculosis,  and  of  malignant  disease  in 
general  the  disproportionate  hemoglobin  loss  may  be  so  decided 
that  the  blood  changes  cannot  be  distinguished  from  those  of 
chlorosis,  and  to  this  condition  the  much-abused  term  "chloro- 
anemia"  has  been  applied. 

The  fact  must  be  emphasized  that  simply  the  hemoglobin  esti- 
mate and  erythrocyte  count  alone  are  absolutely  uncharacter- 
istic in  secondary  anemias,  for  they  may  range  in  the  individual 
case  from  slightly  subnormal  figures  to  an  extreme  degree  of 
oligochromemia  and  oligocythemia.  In  a  patient  studied  by 
von  Limbeck,1  for  example,  at  one  time  the  erythrocytes  num- 
bered only  306,000  per  c.mm.,  but  ultimately  perfect  recovery 
ensued  and  the  count  rose  to  4,280,000.  But  if  averages  are  used 
as  a  basis  for  conclusions,  it  becomes  evident  that  the  hemoglobin 
diminution  is  less  marked  than  in  any  other  blood  disease,  and 
that  the  erythrocyte  loss  is  also  less  than  in  any  other  form  of 
anemia  except  chlorosis.  Data  based  upon  200  examinations  of 
various  types  of  anemia  by  the  writer  give  the  following  results 
regarding  these  points: 


Disease. 

Average  Percentage  of 
Hemoglobin  Loss  in 
50  Consecutive 
Estimates. 

Average  Percentage  of 
Erythrocyte  Loss  in 
50  Consecutive 
Counts. 

Secondary  anemia  

Chlorosis  

Leukemia  

Pernicious  anemia.  

44.8  per  cent. 
54.8  "  " 
60.6  "  " 
74-5  "  " 

27.1  per  cent. 

17.8  "  " 

45-4  "  " 

76.9  "  " 

Examination  of  the  stained  specimen  shows  a  variable  degree 
of  alteration  in  the  shape,  size,  and  general  structure  of  the  cells. 
In  mild  cases  simple  pallor  of  the  erythrocytes  and  perhaps  a 
few  microcytes  and  moderately  misshapen  poikilocytes  are  the 
only  changes  to  be  observed,  erythroblasts,  polychromatophiles, 
and  cells  with  basophilic  stroma  degeneration  being  entirely 
wanting.  In  severe  cases,  with  excessive  oligocythemia,  a  large 
proportion  of  the  cells  are  either  under-  or  over-sized,  the  latter 

1  hoc.  cit. 


298 


DISKASKS   OF   THE  BLOOD. 


forms  appearing  to  prevail  in  relation  to  the  intensity  of  the  ane- 
mic process;  poikilocytosis  and  polychromatophilia  are  sometimes 
extreme,  and  evidences  of  Grawitz's  stroma  degeneration  are 
found,  together  with  a  more  or  less  abundance  of  nucleated  eryth- 
rocytes, the  majority  of  which  conform  to  the  normoblastic  type. 
In  most  instances  normoblasts  only  are  present,  but  rarely  an 
occasional  megaloblast,  implying  a  slight  tendency  toward  a  fetal 
type  of  hemogenesis,  is  also  seen.  The  significance  of  erythro- 
blasts  in  anemia  and  the  circumstances  under  which  they  are 
found  have  been  discussed  in  a  preceding  section.    (See  p.  187.) 

Typical  polynuclear  neutrophile  leucocytosis 
Leucocytes,  is  common,  but  by  no  means  constant,  in  the  sec- 
ondary anemias,  independent  of  their  grade,  for 
the  cellular  increase  is  provoked  by  a  stimulation  of  the  functional 
activities  of  the  marrow,  which  vary  according  to  the  individual 
and  to  the  nature  of  the  exciting  cause.  The  differential  changes 
associated  with  such  a  leucocytosis  (low  percentages  of  lympho- 
cytes and  eosinophiles,  with,  perhaps,  a  few  myelocytes)  have 
already  been  referred  to  in  a  preceding  section.  A  moderate 
leucocytosis  is  especially  common  in  the  anemias  of  children, 
and  in  those  symptomatic  of  inflammatory  and  suppurative  condi- 
tions and  of  malignant  diseases.  While  in  other  anemias,  espe- 
cially those  of  chronic  type,  a  normal  leucocyte  count  or  even 
leucopenia  may  be  found,  often  in  association  with  a  relative 
lymphocytosis,  as  is  frequently  the  case  in  the  anemias  of  enteric 
fever  and  of  tertiary  syphilis. 

The  plaques  are  usually  increased,  but  appa- 
Blood        rently  without  any  constant  relationship  to  the 
Plaques.      degree  of  hemoglobin  and  erythrocyte  loss.  In 
some  cases  these  bodies  may  number  more  than 
double  the  maximum  normal  standard,  as  in  a  case  of  anemia  in 
a  child  with  a  tumor  of  the  spleen,  noted  by  von  Emden,1  in  which 
an  estimate  of  829,000  to  the  c.mm.  was  made. 
1   ^  The  principal  blood  changes  found  in  second- 

ly  DlAGN0SIS-    ary  anemia  are  as  follows: 

Hemoglobin.      Variable  decrease,  usually  somewhat  more  marked 
than  the  erythrocyte  loss ;  color  index  subnormal. 

Erythrocytes.      Variable  decrease. 

Erythroblasts,  in  severe  cases;  normoblasts  out- 
numbering megaloblasts,  which  are  rare. 
Deformities  of  shape  and  size,  polychromato- 
philia, and  basic  staining  of  the  stroma  in  severe 
cases. 

1  Loc.  cit. 


POST-HEMORRHAGIC  ANEMIA. 


299 


Leucocytes.        Commonly  increased;  rarely  leukopenia. 

Polynuclear  neutrophils  usually  increased,  and 
lymphocytes  and  eosinophiles  relatively  dimin- 
ished. 

Lymphocytosis  in  some  cases,  usually  those  of 
severe  type  and  chronic  course. 
Small  numbers  of  myelocytes  sometimes  found. 
Plaques.  Usually  increased. 


V.    POST-HEMORRHAGIC  ANEMIA. 

Among  the  many  underlying  causes  of  acute 
Etiology,  post-hemorrhagic  anemias  may  be  mentioned 
trauma,  abortion,  post-partum  hemorrhage,  epis- 
taxis,  pulmonary  tuberculosis,  peptic  ulcer,  enteric  fever,  visceral 
carcinoma,  hemorrhagic  pancreatitis,  and  the  rupture  of  an  aneu- 
rysm, of  a  Fallopian  tube  during  ectopic  pregnancy,  and  of  a  mass 
of  extensively  varicose  veins.  Chronic  hemorrhages,  such  as  those 
resulting  from  diseases  belonging  to  the  hemorrhagic  diathesis, 
from  hemorrhoids,  or  from  uterine  diseases  usually  give  rise  to  a 
much  less  decided  blood  loss  than  the  first-named  conditions,  but 
in  some  instances  these  factors,  if  persistent,  may  be  sufficient 
eventually  to  provoke  anemia  of  great  intensity. 

Reduction  in  the  total  volume  of  blood,  or 
Efeect  Upon  oligemia,  ensues  as  the  immediate  effect  of  an 
the  Blood,  acute  hemorrhage,  and  a  count  made  immedi- 
ately after  the  blood  loss  may  show  no  reduction 
in  the  hemoglobin  and  corpuscular  value,  since  the  oligemia  af- 
fects the  liquid  and  cellular  elements  proportionately.  As  reac- 
tion sets  in  the  system  attempts  to  compensate  for  the  loss  of 
blood  by  the  rapid  absorption  by  the  capillaries  of  large  amounts 
of  liquids  from  the  tissues,  so  that  the  blood  soon  becomes  highly 
diluted,  or  hydremic.  This  is  evidenced  by  a  proportionate  dimi- 
nution in  the  hemoglobin  percentage  and  erythrocyte  count,  the 
degree  of  this  decrease  depending  upon  the  extent  of  the  hem- 
orrhage. It  is  thought  that  in  many  instances  this  fluid  transfer 
from  tissue  to  vessel  is  inaugurated  immediately  after  or  even 
during  the  hemorrhage,  and  that  the  original  volume  of  blood  is 
restored  within  a  few  hours.  A  further  diminution  in  hemo- 
globin and  erythrocytes  occurs  after  the  normal  volume  of  blood 
has  been  reestablished,  so  that  the  minimum  decrease  is  not  ob- 
served until  some  little  time  has  elapsed  after  the  hemorrhage. 
As  a  rule,  the  minimum  count  is  seen  at  some  period  during  the 


3°° 


D1SKASKS   OF   TIIK  BLOOD. 


first  week  after  the  blood  loss — as  early  as  the  first  or  second  day 
in  some  instances,  but  as  late  as  the  tenth  or  eleventh  day  in 
others.  This  secondary  fall  is  thought  to  depend  upon  the  in- 
troduction into  the  circulation  of  large  numbers  of  immature, 
feebly  resistant  erythrocytes,  which  suffer  rapid  and  premature 
destruction,  and  thus  bring  about  a  disturbance  in  the  equilibrium 
between  the  rate  of  blood  production  and  blood  destruction  in 
favor  of  the  latter.  As  soon  as  the  marrow  is  able  to  meet  the 
drain  in  an  adequate  manner,  by  the  increased  production  of  more 
resistant  cells,  the  anemia  ceases,  and  the  hemoglobin  and  eryth- 
rocyte estimates  begin  to  rise. 

Other  changes  consequent  to  hemorrhage  are  a  diminution  in 
the  corpuscular  volume  in  the  dry  residue  of  the  whole  blood, 
and  in  the  proteids  of  the  serum.  The  serum  solids  and  fibrin- 
forming  elements  are  apparently  increased.  Despite  the  loss  of 
albumin,  Haesslin1  found  a  constant  fall  in  the  freezing-point  of  the 
blood. 

Authorities  differ  as  to  the  degree  of  blood  loss  which  man  is 
capable  of  surviving,  a  difference  which  is  but  natural  when  it  is 
remembered  that  factors  other  than  the  actual  amount  of  blood 
lost,  conspicuous  among  which  are  the  age,  sex,  and  resisting 
powers  of  the  patient,  are  all  important  in  determining  the  fatality 
of  the  hemorrhage.  According  to  Immermann,2  hemorrhages  in- 
volving a  loss  of  one -half  of  the  total  bulk  of  blood  in  the  body 
invariably  prove  fatal.  Hayem3  is  authority  for  the  statement 
that,  as  a  general  rule,  recovery  is  possible  when  the  total  volume 
of  blood  lost  does  not  exceed  one-eighteenth  of  the  individual's 
body- weight.  This  author  has  reported  the  most  astonishing 
example  on  record  of  post-hemorrhagic  cellular  decrease,  in 
which  he  observed  a  diminution  in  the  erythrocytes  to  n  per 
cent,  of  normal  in  a  case  of  post-partum  hemorrhage,  with  sub- 
sequent recovery  of  the  patient.  Behier4  has  described  a  case 
of  metrorrhagia  in  which  recovery  occurred  in  spite  of  a  reduc- 
tion in  the  erythrocytes  to  19  per  cent,  of  normal.  Laache5  has 
recorded  a  number  of  instances  in  which  the  corpuscular  esti- 
mates fell  below  50  per  cent,  of  normal— in  one  case  to  32  per  cent. 
These  last  three  examples  are  sufficient  to  disprove  the  former 
belief  that  death  inevitably  ensues  when  the  corpuscular  loss,  as 
the  result  of  hemorrhage,  falls  as  low  as  50  per  cent,  of  normal. 

Increase  in  the  number  of  leucocytes,  usually  of  moderate  de- 
gree, promptly  develops  in  the  great  majority  of  cases  and  per- 

1  Deutsch.  Arch.  f.  klin.  Med.,  1902,  vol.  lxxiv,  p.  577. 

2  Cited  by  Rieder,  loc.  cit.  3  Loc.  cit. 

*  Cited  by  Laache,  loc.  cit.  5  "Die  Anamie,"  Christiania,  1888. 


POST- HEMORRHAGIC  ANEMIA. 


3OI 


sists  for  several  days.  It  usually  involves  an  absolute  and  rela- 
tive gain  in  the  polynuclear  neutrophile  cells,  with  a  consequent 
decrease  in  the  mononuclear  forms,  but,  rarely,  the  reverse  may 
be  noted.  In  fatal  cases  this  increase  may  not  occur;  nor,  ac- 
cording to  Baumann,1  does  it  occur  after  hemorrhage  during  the 
adminstration  of  arsenic,  the  leucocytes  in  such  instances  diminish- 
ing. This  investigator  also  found  that  the  giving  of  arsenic  and 
inorganic  iron  to  animals  experimentally  bled  resulted  in  slighter 
blood  deterioration  than  when  either  drug  was  used  alone. 

The  maximum  count  is  commonly  attained  within  a  few  hours 
after  the  onset  of  the  leucocytosis,  the  normal  being  regained 
within  a  week  or  less.    (See  p.  246.) 

The  blood  plaques  are  strikingly  increased  after  hemorrhage. 
The  coagulability  of  the  blood  is  abnormally  quick,  being  more 
rapid  in  profuse  than  in  moderate  hemorrhages. 

Following  the  reestablishment  of  the  normal 
Regenera-  blood  volume,  regeneration  of  the  erythrocytes 
tion.  and  hemoglobin  and  a  consequent  dissipation  of 
the  hydremia  ensue.  The  time  necessary  for 
the  completion  of  this  process  varies  greatly  in  different  individ- 
uals, as  the  rapidity  with  which  blood  regeneration  occurs  depends 
upon  different  factors,  such  as  the  extent  of  the  original  hemor- 
rhage and  the  age  and  natural  regenerative  powers  of  the  patient. 
The  latter  are  at  their  maximum  during  the  third  and  fourth 
decades  of  life,  at  their  minimum  during  infancy  and  old  age,  and 
are  regarded  as  more  active  in  women  than  in  men.  The  exist- 
ence of  a  well-developed  cachexia  or  an  infectious  disease,  as 
well  as  the  neglect  of  proper  treatment  of  the  hemorrhage,  are 
obstacles  which  retard  the  regeneration  of  the  blood  to  its  normal 
composition.  The  process  appears  to  be  more  active  if  trans- 
fusion of  a  normal  saline  solution  has  been  practised  than  in  un- 
treated cases,  the  rapidity  of  the  gain  being  especially  striking 
during  the  latter  half  of  the  regeneration  period.  The  transfusion 
of  blood  hastens  regeneration  even  more  decidedly.  Otto 2  and 
Hall  and  Eubank 3  have  shown  experimentally  in  animals,  bled 
and  given  transfusions  of  artificial  serum,  that  regeneration  once 
stimulated  into  activity  may  carry  the  blood,  quantitatively,  con- 
siderably beyond  the  established  normal  standard. 

In  uncomplicated  cases,  according  to  Bierfreund,4  regeneration 
is  effected  within  four  weeks  if  the  hemorrhage  produces  a  hemo- 

1  Jour.  Physiol.,  1903,  vol.  xxix,  p.  18. 

2  Pfluger's'Arch.,  1885,  vol.  xxxv,  p.  57. 

3  Jour.  Exper.  Med.,  1896,  vol.  i,  p.  656. 

4  Langenbeck's  Arch.,  1890-91,  vol.  xli,  p.  1. 


3°2 


DISEASES  OF  THE  BLOOD. 


globin  loss  of  25  per  cent.,  and  in  about  three  weeks  if  the  loss 
does  not  exceed  20  per  cent.  The  latter  period  may  be  regarded 
as  the  average  regeneration  time  in  the  great  majority  of  instances. 

As  regeneration  proceeds  the  hemoglobin  and  corpuscular 
deficiencies  gradually  become  less  conspicuous,  but  the  increase 
in  these  two  constituents  does  not  occur  along  parallel  lines. 
The  increase  in  the  number  of  erythrocytes  is  much  more  rapid 
than  the  gain  in  the  hemoglobin  percentage,  which  usually 
remains  subnormal  for  some  time  after  the  normal  number  of 
corpuscles  has  been  reestablished.  Owing  to  this  lagging  behind 
of  the  hemoglobin  low  color  indices  are  the  rule.  Faulty  hemo- 
genesis,  owing  to  which  the  great  majority  of  the  erythrocytes 
are  deficient  in  hemoglobin  and  many  of  them  of  abnormally  small 
size,  serves  best  to  explain  this  slow  restitution  of  the  hemoglobin 
value. 

The  appearance  in  the  blood  of  normoblasts  is  common  after 
hemorrhage,  and  in  rare  instances  an  occasional  megaloblast  and 
atypical  erythroblast  may  be  observed.  According  to  Ehrlich,1 
if  thorough  and  systematic  search  is  made,  normoblasts  may 
be  constantly  found  after  the  second*  or  third  day  following  the 
blood  loss  until  the  regeneration  of  the  blood  is  complete.  The 
transient  appearance  of  large  numbers  of  normoblasts,  known 
as  "blood  crises,"  has  been  already  described.  (See  p.  189.) 
Dawson,2  who  has  carefully  studied  the  effects  of  venous  hemor- 
rhage in  dogs,  found  no  evidence  of  any  close  relation  between 
the  number  of  erythroblasts  and  the  rapidity  and  character  of 
the  regeneration  of  the  hemoglobin  and  erythrocytes.  In  severe 
cases  polychromatophilia  of  the  erythrocytes  may  be  noted,  this 
sign  first  becoming  apparent  as  early  as  the  first  day  after  the 
hemorrhage,  and  gradually  disappearing  as  regeneration  is  effected. 
Deformities  in  the  size  and  shape  of  the  erythrocytes  are  not 
uncommon,  of  which  microcytes  constitute  the  most  frequent 
example.  Large  hydropic  megalocytes  and  poikilocytes  are  met 
with  more  rarely. 


VI.  LEUKEMIA. 

According  to  the  classification  in  general  vogue 
Varieties,    at  the  present  time  two  clinical  varieties  of  leu- 
kemia, the  myelogenous  or  spleno -medullary  and 
the  lymphatic,  are  recognized.    The  myelogenous  variety,  which 
is  almost  invariably  a  chronic  process,  is  associated  with  a 

1  Loc.  cit.  2  Amer.  Jour.  Physiol.,  1900,  vol.  iv,  p.  2. 


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303 


DISEASES  OF  THE  BLOOD. 


marked  proliferation  of  myeloid  tissue,  and  is  characterized  by 
a  striking  myelemia  and  generally  by  conspicuous  enlargement 
of  the  spleen,  with  little  or  no  involvement  of  the  lymphatic  glands. 
The  lymphatic  form,  which  may  run  either  an  acute  or  a  chronic 
course,  more  commonly  the  latter,  is  a  process  associated  with 
a  proliferation  of  lymphoid  tissue,  and  is  characterized  by  a 
blood  picture  known  as  lymphemia,  and  in  the  great  majority 
of  cases  by  marked  enlargement  of  the  lymphatic  glands,  with 
moderate  involvement  of  the  spleen.  But  these  two  clinical  pic- 
tures, in  so  far  as  they  relate  to  the  splenic  and  lymphatic  hyper- 
trophy, are  by  no  means  constant,  for,  although  cases  of  mye- 
logenous leukemia  always  have  enlarged  spleens,  exceptionally 
they  may  also  have  decided  lymphatic  hyperplasia.  Furthermore, 
cases  of  lymphatic  leukemia  are  occasionally  encountered  in  which 
there  is  a  marked  splenic  tumor  without  demonstrable  signs  of 
lymphatic  enlargement,  as  well  as  those  in  which  the  bone  marrow 
alone  is  involved  without  implication  of  either  the  spleen  or  the 
lymphatic  glands.  To  this  group  belong  the  acute  leukemias 
with  myelogenous  lesions  described  by  Miiller,1  Walz,2  Pappen- 
heim,3  Michalis,4  Dorothy  Reed,5  A.  O.  J.  Kelly,6  and  others- 
studies  which  tend  to  upset  Ehrlich's  theory  that  lymphatic  leu- 
kemia is  essentially  a  lesion  of  the  lymph  glands.  Because  of 
such  atypical  examples,  the  gross  appearance  of  the  spleen  and 
lymphatics  must  be  regarded  as  a  sign  of  distinctly  secondary 
importance  to  the  blood  picture,  which  is  alone  the  tangible  diag- 
nostic clue. 

Gerhardt,7  Fleischer  and  Penzoldt,8  and  Wey 9  report  cases  of 
the  apparent  transition  of  myelogenous  into  lymphatic  leukemia 
and  into  pernicious  anemia.  These  so-called  conversions  of  type 
may  really  represent  merely  the  superposition  of  a  leucocytosis 
sufficiently  great  temporarily  to  dominate  the  blood  picture.  If 
such  were  the  case,  it  is  obvious  that  with  the  disappearance  of  the 
leucocytosis  the  true  character  of  the  blood  changes  will  become 
apparent — in  the  first  instance,  a  lymphocytosis,  and  in  the  second, 
a  megaloblastic  anemia. 

Of  the  two  forms  of  the  disease,  the  myelogenous  is  much  the 
commoner.    In  the  series  of  42  cases  of  leukemia  which  the 

1  Centralbl.  f.  dig.  Path.  u.  path.  Anat.,.  1894,  vol.  v,  pp.  553  and  601. 

2  Ibid.,  1901,  vol.  xii,  p.  967. 

3  Virchow's  Arch.,  1899,  vol.  clvii,  p.  19;  ibid.,  1900,  vol.  clix,  p.  40;  ibid., 
1901,  vol.  clxi,  p.  424. 

4  Deutsch.  med.  Wochenschr.,  1901,  vol.  xxvii,  p.  651. 

5  Amer.  Jour.  Med.  Sci.,  1902,  vol.  cxxiv,  p.  653. 

6  Trans.  Assoc.  Amer.  Phys.,  1903,  vol.  xviii,  p.  481. 

7  Deutsch.  Arch.  f.  klin.  Med.,  1880,  vol.  xxvi,  p.  368. 

8  Ibid.,  1896,  vol.  lxvii,  p.  300.  9  XV.  Cong.  f.  inn.  Med.,  1897. 


LEUKEMIA. 


305 


writer  has  had  the  opportunity  of  studying,  29  were  of  the  myelog- 
enous and  13  of  the  lymphatic  form;  while  of  Cabot's  66 
cases,1  49  were  myelogenous  and  17  lymphatic — a  proportion 
of  almost  three  of  the  former  to  one  of  the  latter,  for  the  combined 
series  of  108  cases. 

In  the  present  state  of  our  knowledge  it  is 
Parasitology,  not  possible  to  regard  leukemia  as  a  disease  of  in- 
fectious origin,  notwithstanding  the  suggestive- 
ness  of  the  symptoms  shown  by  many  of  those  cases  which  run 
an  acute  course.  Within  the  past  few  years  several  investigators, 
notably  Delbert,2  Kelsch  and  Vaillard,3  Pallowski,4  and  Lowit5 
have  attempted  to  ascribe  to  various  micro-organisms  specific 
etiological  relationship  with  the  condition,  but  these  attempts 
have  thus  far  been  unconvincing.  Lowit' s  researches,  however, 
are  worthy  of  special  attention,  if  for  no  other  reason  than  for 
the  elaborate  and  painstaking  study  which  they  represent.  This 
author  believes  that  two  distinct  forms  of  parasites  may  be  dem- 
onstrated in  leukemia:  the  Hcemamoeba  leukemia  magna,  thought 
to  be  the  specific  cause  of  the  myelogenous  form  of  the  disease, 
and  the  Hoemamceba  leukemia  parva,  which  he  claims  is  the 
definite  infective  principle  of  the  lymphatic  form.  These  so-called 
"specific  bodies,"  which  are  found  both  in  the  blood  of  the 
peripheral  vessels  and  in  the  hematopoietic  organs,  have  either 
a  granular  or  an  ameboid  appearance,  and  bear  a  more  or  less 
close  resemblance  to  the  basophile  granules  of  the  leucocytes; 
navicular,  segmenting,  and  vacuolated  forms  are  also  said  to 
occur.  They  are  either  attached  to  or  lie  within  the  leucocytes, 
especially  the  small  lymphocytes,  and  more  rarely  the  other  varie- 
ties of  normal  leucocytes  and  the  myelocytes;  in  an  occasional 
instance  they  are  said  to  be  found  lying  free  in  the  plasma.  Al- 
though it  is  claimed  that  a  leucocytic  infection  has  been  produced 
in  animals  by  the  injection  of  blood  presumably  containing  these 
micro-organisms,  all  attempts  to  cultivate  them  on  artificial  media 
have  proved  futile.  Lowit's  amebae  are  demonstrated  only  in  heat- 
fixed  specimens,  stained  preferably  with  a  steaming  hot  solution 
of  Lofner's  methylene -blue,  after  which  they  are  washed,  differ- 
entiated with  a  0.3  per  cent,  solution  of  hydrochloric  acid  alcohol, 
again  washed,  and  mounted.  In  specimens  thus  treated  they  stain 
metachromatically,  and,  if  the  acid  alcohol  differentiation  has 
been  properly  effected,  are  the  only  elements  except  the  basophile 

1  Loc.  cit.  2  Bull,  et  mem.  Soc.  de  chir.,  Paris,  1895,  vol.  xxi,  p.  788. 

3  Annal.  de  l'lnstitut  Pasteur,  1890,  vol.  iv,  p.  276. 

4  Deutsch.  med.  Wochenschr.,  1892,  vol.  xviii,  p.  641. 

5  "Die  Leukamie  als  Protozoeninfektion,"  Wiesbaden,  1900.' 

20 


306 


DISEASES  OF  THE  BLOOD. 


leucocyte  granules  which  retain  the  color  of  the  dye.  Turk,1  who 
has  followed  out  Lowit's  technic  precisely,  in  investigating  this 
author's  claims  has  come  to  the  conclusion  that  these  "  specific 
bodies"  are  in  no  sense  of  parasitic  nature,  but  merely  artefacts 
resulting  from  the  action  of  an  aqueous  solution  of  a  basic  dye 
upon  the  mast  cell  granules,  which  causes  the  partial  solution  of 
the  latter  elements  and  deforms  them.  Turk  claims,  furthermore, 
that  these  so-called  amebae  can  be  produced  both  in  the  normal 
blood  of  man  and  in  the  blood  of  rabbits. 

Myelogenous  Leukemia. 
The  drop  as  it  flows  from  the  puncture  is,  in 
Appearance  most  instances,  of  a  bright  scarlet  color,  and 
of  the       often  has  a  peculiar  and  misleading  appearance 
Fresh  Blood,  of  density.     After  brief  exposure  to  the  air, 
it  may  become  resolved  into  a  serous,  scarlet 
fluid,  in  which  are  suspended  many  minute,  whitish,  fat-like 
masses;  the  former  appears  to  consist  of  serum  and  erythro- 
cytes, and  the  latter  of  adhering  masses  of  leucocytes.    It  was 
probably  this  striking  appearance  of  the  leukemic  blood  drop 
that  led  Hughes  Bennett  erroneously  to  describe  the  condition 
as  a  "suppuration  of  the  blood"  before  he  proposed  the  more 
suitable  term  leucocythemia.    In  some  cases  the  drop  is  simply 
much  darker  than  normal,  but  it  is  difficult  to  believe  that  it  ever 
resembles  the  chocolate -brown  shade  mentioned  by  some  authors 
as  occurring  in  this  disease.    The  blood  usually  flows  very  freely 
from  the  wound,  often  by  fine  jets  and  spurts,  especially  if  slight 
pressure  is  applied  above  the  site  of  the  puncture. 

Microscopically,  the  field  is  found  to  contain  an  enormous 
number  of  leucocytes,  the  proportion  of  these  cells  to  the  ery- 
throcytes being,  by  actual  count,  as  great  as  i  to  8  or  6,  or  even 
greater.  Many  different  varieties  of  leucocytes  may  be  distin- 
guished in  the  fresh  specimen,  the  most  striking  being  the  large, 
mononuclear,  finely  granular  cells  of  round  or  ovoid  shape.  These 
are  the  myelocytes  which  are  present  in  enormous  numbers  in 
this  form  of  leukemia,  of  which  they  form  a  characteristic  blood 
picture.  " Fractured"  leucocytes,  usually  eosinophiles,  with  a 
cloud  of  escaped  granules  free  in  the  plasma  in  the  neighborhood 
of  the  disrupted  cell  body,  may  also  be  observed  in  variable  num- 
bers, although  such  cells  are  more  numerous  in  the  dried,  stained 
film.    (See  Figs.  54  and  55.) 

The  erythrocytes  vary  in  number  and  in  appearance  according 

1  XVIII.  Cong.  f.  inn.  Med.,  Wiesbaden,  1900. 


Spleno-Medullary  Leukemia. 
( Triacid  Stain.) 

1.  Small  Lymphocyte. 

2.  Large  Lymphocyte. 

Contrast  this  cell  with  the  myelocytes,  10,  it,  and  12,  noting  the  presence  of  neutro- 
phil granules  in  the  latter,  and  their  absence  in  the  lymphocyte.  The  size  and 
nuclear  characteristics  of  all  these  cells  are  practically  the  same. 

3.  4.  Polynuclear  Neutrophiles. 

5.  Eosinophile. 

In  this  "dwarf"  eosinophile,  ruptured  during  the  preparation  of  the  specimen,  the 
granules  are  peculiarly  arranged  about  the  nucleus;  no  signs  of  protoplasm  are  dis- 
tinguishable. 

6.  Eosinophilic  Myelocyte. 

Note  the  irregularity  with  which  the  granules  are  stained. 

7.  8,  9,  10,  ii,  12,  13,  14,  15.  Myelocytes.  {Neutrophilic.) 

These  cells  vary  greatly  in  size  (compare  8  with  9),  but  they  all  have  similar  distinc- 
tive characteristics — a  large  opalescent  nucleus  containing  a  scanty  chromatin  net- 
work embedded  in  a  cell  body  crowded  with  delicate  neutrophile  granules,  precisely 
like  those  found  in  the  polynuclear  neutrophiles,  3  and  4.  The  nucleus  of  7  is  dis- 
tinctly ipdented  and  somewhat  denser  than  that  of  the  other  myelocytes.  This  cell 
probably  represents  a  developmental  phase  of  the  myelocyte  just  short  of  its  transi- 
tion into  a  typical  polynuclear  neutrophile. 
16.  Normoblast. 

The  erythrocytes  (stained  orange)  show  many  evidences  of  deformity,  an  occasional 
megalocyte,  many  microcytes,  and  a  few  poikilocytes  being  present.  Polychromato- 
philia  is  absent. 

(E.  F.  Faber,  fee.) 


BlUYEsiS 


I 


LEUKEMIA. 


3°7 


to  the  severity  of  the  coexisting  anemia;  in  some  instances  large 
numbers  of  poikilocytes,  megalocytes,  and  microcytes,  with 
marked  pallor  of  the  corpuscles,  may  be  seen,  while  in  others 
the  changes  affecting  the  erythrocytes  appear  to  be  but  trifling. 

In  fresh  films  which  have  been  allowed  to  dry  for  some  time 
Charcot-Leyden  crystals  may  sometimes  be  detected.  They  ap- 
pear as  colorless,  refractive  crystals,  shaped  like  octahedra,  having 
long,  pointed,  sharp  angles,  and  occurring  either  singly  or  in 
twos  or  threes,  superimposed  at  right  angles  or  as  collections 
of  radiating,  crystalline  masses.  These  crystals  are  not  observed 
in  the  freshly  drawn  blood,  being  demonstrable  only  in  films 
which  have  stood  exposed  to  the  air  for  at  least  twenty-four  hours, 
and  only  occasionally  even  under  this  circumstance. 

On  account  of  the  presence  in  the  blood  of  such  large  numbers 
of  leucocytes  a  very  small  drop  should  be  used  for  making  the 
cover-glass  spreads  for  staining,  since  it  is  advisable  to  avoid 
overcrowding  the  field  with  these  cells.  No  difficulty  will  be  ex- 
perienced in  obtaining  thin,  evenly  distributed  spreads  if  this  pre- 
caution is  observed,  especially  if  the  cover-glasses  are  slightly 
warmed  just  before  they  are  used. 

The  coagulation  of  the  blood  and  the  for- 
Coagulation.  mation  of  the  fibrin  network  must  be  regarded  as 
variable.  In  some  cases,  especially  those  with 
great  loss  of  hemoglobin  and  erythrocytes,  both  processes  are  de- 
layed and  imperfect,  as  evidenced  by  the  formation  of  the  "rasp- 
berry-jelly" clots  referred  to  by  the  German  writers.  But  in 
other  cases  the  coagulation  time  is  unaltered,  and  the  fibrin  net- 
work is  perfectly  normal. 

The  alkalinity  of  the  blood  is  usually  de- 
Alkalinity.  creased,  and,  as  in  chlorosis,  it  increases  after  the 
patient  is  given  iron,  in  parallelism  with  the  gain 
in  hemoglobin  and  erythrocytes.  In  3  cases  studied  by  Burmin1 
an  average  alkalinity  equivalent  to  146  mgm.  was  found,  Landois' 
method  being  employed  in  the  investigations.  Taylor 1  found  an 
average  of  380  mgm.  in  three  tested  by  the  von  Limbeck  method. 

In  cases  with  severe  anemia  the  density  of  the 
Specific     blood  may  fall  as  low  as  1.035  or  1-040.  Gra- 
Gravity.     witz1  has  reported  a  case  in  which  the  figure  was 
1.023.    The  fallacies  in  leukemia  of  Hammer- 
i  schlag's  tables  of  specific  gravities  and  their  hemoglobin  equiva- 
lents have  already  been  pointed  out.    (See  p.  133.) 

1  Loc.  cit. 


3o8 


DISKASKS   OK   TI1K  BLOOD. 


Decided  hemoglobin  and  erythrocyte  loss  is 
Hemoglobin  the  invariable  rule  sooner  or  later  during  the 
and  course  of  the  disease,  the  anemia  usually  being 
Erythrocytes,  well  defined  at  the  time  the  patient  first  comes 
under  observation,  and  becoming  acutely  marked 
as  the  termination  of  the  illness  approaches.  It  is  generally  the 
case  that  the  hemoglobin  loss  is  disproportionately  greater  than 
the  decrease  in  the  erythrocytes,  thus  producing  a  moderately 
low  color  index,  but  in  some  cases  just  the  opposite  of  this  is  ob- 
served.1 In  the  writer's  29  cases,  grouped  in  Table  VIII,  the 
color  index  averaged  about  0.86.  The  hemoglobin  percentage 
ranged  between  24  and  70,  averaging  48.6,  and  the  number  of 
erythrocytes  was  as  low  as  572,000  and  as  high  as  4,200,000  per 
c.mm.,  the  mean  average  being  2,814,000;  the  count  of  these 
cells  was  diminished  to  one-half  of  the  normal  standard,  or  below 
this  figure,  in  11  of  the  cases  examined.  An  analysis  of  Cabot's 
series  of  42  cases  of  myelogenous  leukemia2  shows  these  average 
findings:  hemoglobin,  43  per  cent.;  erythrocytes,  3,123,000  per 
c.mm.;  and  color  index,  about  0.68. 

TABLE  VIII.— HEMOGLOBIN  AND  ERYTHROCYTES  IN  29  CASES 
OF  MYELOGENOUS  LEUKEMIA. 

Hemoglobin                        Number  of  Erythrocytes  Number  of 

Percentage.                           Cases.  per  c.mm.  Cases. 

From  60-70                              7  From  4,000,000-5,000,000   1 

"     50-60                             5  "     3,000,000-4,000,000  15 

"     40-50                             5  "     2,000,000-3,000,000   8 

"     30-40  10  "     1,000,000-2,000,000  t  4 

"     20-30                               2  Below  1,000,000   1 

Average,      48.6  per  cent.  Average,      2,814,000  per  c.mm. 

Maximum    70.0  "     "  Maximum,  4,200,000  " 

Minimum,    24.0  "     "  Minimum,      572,000  "  " 

Fluctuations  in  the  hemoglobin  percentage  and  in  the  number  of 
erythrocytes  may  or  may  not  accompany  variations  in  the  leuco- 
cyte count.  Sometimes,  as  the  leucocytes  rise,  the  erythrocytes 
fall,  but  again  they  remain  practically  stationary;  or,  the  leuco- 
cytes may  progressively  fall  to  a  comparatively  moderate  count, 
coincidentally  with  an  apparent  improvement  in  the  patient's  gen- 
eral condition,  and  yet  the  erythrocytes  do  not  materially  gain  in 
numbers.    Taylor 3  refers  to  two  such  instances  which  have  come 

1  It  is  to  be  remembered  that  hemoglobin  estimates  in  leukemia  may  be  unreli- 
able (except  when  Dare's  instrument  is  used),  for  correct  readings  are  sometimes 
impossible,  owing  to  the  milkiness  of  the  diluted  blood  from  the  presence  of  such 
immense  numbers  of  leucocytes.  About  one-half  of  the  hemoglobin  figures  in  the 
accompanying  table  (Table  VIII)  were  obtained  by  means  of  von  FleischTs  heni- 
ometer,  the  remainder  being  based  upon  examinations  with  Oliver's  and  with 
Dare's  instruments. 

2  Loc.  cit.  3  Loc.  at. 


LEUKEMIA. 


under  his  observation,  in  both  of  which  the  blood  picture  at  cer- 
tain brief  intervals  resembled  that  of  pernicious  anemia,  for  under 
the  influence  of  energetic  arsenical  treatment  the  leucocytes  were 
reduced  to  normal,  while  the  oligocythemia  stubbornly  persisted. 
In  a  case  studied  for  a  protracted  period  it  is  possible  to  distin- 
guish a  general  decrease  in  the  erythrocyte  count  as  the  leuco- 
cytes increase,  although  the  reverse  may  not  be  true.  (See  Chart 
II,  p.  311.) 

Examination  of  the  stained  specimen  shows  the  presence  of 
nucleated  erythrocytes  in  practically  every  case  of  myelogenous  leu- 
kemia, these  cells  often  being  many  times  more  numerous  than 
in  grave  cases  of  pernicious  anemia.  Normoblasts  prevail, 
always  being  more  numerous  than  megaloblasts ;  in  some  cases 
they  are  the  only  type  of  erythroblast  to  be  observed;  in  others 
they  are  associated  with  a  relatively  moderate  number  of  typical 
megaloblasts,  or,  more  commonly,  with  large  numbers  of  atypical 
.forms,  sharing  the  characteristics  of  the  typical  adult  and  em- 
bryonic nucleated  erythrocytes.  In  the  9  cases  of  this  variety  of 
leukemia  in  which  the  writer  has  made  differential  erythrocyte 
counts  the  following  estimates  were  obtained  at  the  first  exami- 
nations : 


Number. 

Total  Number  of 
Erythroblasts  per  c.mm. 

Normoblasts 

PER  C.MM. 

Megaloblasts 

PER  C.MM. 

I 

12,913 

8376 

4537 

2 

9,178 

9178 

0 

3 

8,626 

7264 

1362 

4 

8,064 

6048 

2016 

5 

5.694 

3504 

2190 

6 

3>234 

1848 

1386 

7 

2,940 

2940 

0 

8 

1,980 

.  1980 

0 

9 

748 

748 

0 

Average : 

5>93* 

4654 

1277 

Comparison  of  the  above  summary  with  the  table  giving  the 
number  and  forms  of  erythroblasts  in  pernicious  anemia  (Table 
V,  p.  283)  illustrates  two  striking  facts  concerning  these  cells 
in  myelogenous  leukemia:  the  immense  numbers  in  which  they 
occur  and  the  predominance  of  normoblasts  over  megaloblasts. 
Periods  of  temporary  improvement  in  the  patient's  general  health 
are  often  heralded  by  a  notable  increase  in  the  normoblasts, 
but  it  is  a  noteworthy  fact  that  during  these  remissions,  while  the 
leucocytes  may  fall  decidedly,  the  normoblasts  tend  to  persist 
in  greater  or  less  numbers. 

Examples  of  so-called  nuclear  extrusion,  of  multinucleation, 


DISKASKS   OK   TIIK  BLOOD. 


of  clovcr-leaf,  dumb-bell,  or  other  irregularly  formed  nuclei,  and 
even,  in  rare  instances,  of  karyokinesis  are  observed  in  many  of  the 
normoblasts.  (See  Fig.  49,  p.  193.)  Such  alterations  may  be  more 
conspicuous  in  highly  developed  cases  of  myelogenous  leukemia 
than  in  any  other  disease  of  the  blood.  In  an  occasional  normoblast 
the  contracted,  glistening,  intensely  basic  nucleus  is  highly  sugges- 
tive of  pyknosis.  No  one  who  has  done  much  blood  work  can 
fail  to  be  struck  with  the  obvious  avidity  displayed  by  the  stroma 
of  the  erythroblasts  for  the  acid  fuchsin  of  the  triple  stain,  a 
peculiarity  which  is  exhibited  in  spite  of  good  technic  and  the 
use  of  a  reliable  staining  solution. 

Dejormities  affecting  the  size  and  the  shape  of  the  erythrocytes 
may  be  trivial  or  decided,  depending  upon  the  degree  of  hemo- 
globin and  erythrocyte  loss  present.  Polychromatophilia,  alone 
or  associated  with  basophilic  stroma  degeneration,  is  very  com- 
mon in  cases  with  great  anemia,  these  changes  affecting  both 
the  nucleated  and  the  non-nucleated  cells. 

TABLE  IX.— NUMBER  OF  LEUCOCYTES  IN  29  CASES  OF  MYE- 
LOGENOUS LEUKEMIA. 


Leucocytes  Number  of 

per  c.mm.  Cases. 

Above  1,000,000  t 

From     500,000-1,000,000  5 

"       400,000-  500,000  4 

"        300,000-  400,000  4 

"        200,000-  300,000  6 

"        100,000-  200,000  6 

50,000-  100,000  2 

Below      50,000  1 


Average,        355,119  per  c.mm. 
Maximum,  1,046,000  "  " 
Minimum,       44,000  "  " 

Striking  increase  in  the  number  of  leucocytes 
Leucocytes,  is  found  even  during  the  early  stages  of  the  dis- 
ease. Counts  in  excess  of  100,000  are  generally 
expected,  while  in  fully  70  per  cent,  of  cases  they  exceed  300,000 
and  in  about  20  per  cent.,  500,000  or  higher.  In  rare  instances 
the  number  of  leucocytes  may  be  as  high  as  1,000,000  per  c.mm. 
One  case  of  the  writer's  had  1,046,000  leucocytes.  The  leucocyte 
count  may,  very  infrequently,  equal  or  even  exceed  that  of  the 
erythrocytes,  and  it  is  easy  to  see  that  such  a  condition  is  possible, 
should  the  accompanying  oligocythemia  be  intense.  In  a  patient 
recently  admitted  to  the  Jefferson  Hospital  the  leucocytes  numbered 
650,000  and  the  erythrocytes  572,000.  In  the  estimates  given 
in  Table  IX,  showing  the  number  of  leucocytes  at  the  time  the 
patient  first  applied  for  treatment,  the  average  count  was  355,119 
per  c.mm.,  the  highest  being  1,046,000  and  the  lowest  44,000. 


mmmvi  »i  ill,  ta 


CHART  II. 


SPLENO- 
Red,  Hemoglobin. 


MEDULLARY  LEUKEMIA. 

Black,  Erythrocytes.  Blue,  Leucocytes. 


LEUKEMIA. 


The  number  of  leucocytes  may  fluctuate  enormously  at  various 
times  during  the  progress  of  the  disease,  a  gain  or  a  loss  of  some 
200,000  cells  to  the  c.mm.  from  week  to  week  being  a  matter  of 
common  occurrence.  Sometimes  they  are  temporarily  dimin- 
ished as  the  result  of  the  administration  of  arsenic  to  the  point 
of  tolerance,  or  of  the  vigorous  employment  of  other  therapeu- 
tical measures;  sometimes  the  decrease  takes  place  independ- 
ently of  the  influence  of  remedial  agencies,  so  far  as  can  be  deter- 
mined. When  arsenic  is  withheld,  the  number  of  leucocytes 
promptly  increases,  and  in  spite  of  its  use  they  ultimately  increase 
as  the  disease  runs  its  fatal  course.  The  relations  of  the  leuco- 
cytes' fluctuations  to  the  number  of  erythrocytes  have  already 
been  mentioned.  Hayek1  has  drawn  attention  to  the  fact  that  in 
the  leukemic  individual  the  morning  leucocyte  count  may  be 
greater  by  more  than  100,000  cells  per  c.mm.  than  the  estimate 
made  during  the  afternoon,  and  vice  versa.  In  a  case  in  Pro- 
fessor Wilson's  wards  at  the  Jefferson  Hospital  the  writer  has 
been  able  to  verify  this  statement,  the  counts  being  as  follows: 
11  a.m.,  144,000;  6  p.m.,  256,000 — a  difference  of  112,000  cells 
within  a  period  of  seven  hours.  The  influences  of  digestion 
and  other  sources  of  error  were,  of  course,  excluded  in  making 
this  observation.  The  occurrence  of  this  enormous  diurnal 
fluctuation  emphasizes  the  importance  of  making  the  blood  ex- 
amination of  leukemic  patients  at  precisely  the  same  hour  each 
day  in  cases  studied  for  a  long  period. 

TABLE   X.— QUALITATIVE  CHANGES   IN  THE  LEUCOCYTES  IN 
29  CASES  OF  MYELOGENOUS  LEUKEMIA. 


Average.  Maximum.  Minimum. 

Small  lymphocytes                   4.1  12.0  0.7 

Large  lymphocytes                   9.5  28.4  0.3 

Polynuclear  neutrophils  54.3  77.0  34-1 

Eosinophiles                            5.4  28-7  I-2 

Myelocytes   20.6  44.0  7.0 

Mast  cells 2                             9.0  28.0  1.0 


The  possibility  of  encountering  a  case  of  leukemia  during  a 
period  of  remission,  when  the  typical  blood  changes  are  absent, 
must  be  borne  in  mind,  for  such  instances  are  observed  from  time 
to  time,  although  they  are  very  rare.  For  example,  McCrae3 
reports  a  case,  treated  by  arsenic,  in  which  twice  during  a  period 
of  ten  months  the  blood  and  general  symptoms  of  the  patient 
were  typical  of  myelogenous  leukemia,  and  twice  were  abso- 
lutely normal.  When  first  examined,  this  patient's  leucocytes 
numbered   584,000   per  c.mm.,  three  months   later  they  had 

1  Wien.  klin.  Wochenschr.,  1897,  vol.  x,  p.  475. 

2  Estimates  in  19  cases.  3  Brit.  Med.  Jour.,  1900,  vol.  i,  p.  760. 


312 


DISEASES  OF  THE  BLOOD. 


fallen  to  9250,  two  months  after  this  they  had  risen  to  178,000, 
and  after  a  lapse  of  another  five  months  they  again  fell  to  5000. 
These  fluctuations  did  not  depend  upon  the  influence  of  any  in- 
tercurrent infection  (see  below),  and  the  case  is  peculiar  in  that 
the  leucocytes,  as  well  as  the  erythrocytes,  not  only  were  normal 
in  number,  but  also  normal  qualitatively,  and  in  that  the  patient's 
splenic  tumor  entirely  disappeared  during  the  periods  of  remis- 
sion. A  similar  case  (myelogenous)  is  reported  by  Simon  and 
Campbell,1  in  which  the  leucocytes,  after  vigorous  arsenical  treat- 
ment for  three  weeks,  fell  from  350,000  to  4000,  with  disappearance 
of  the  myelemic  blood  picture  and  of  the  splenic  tumor.  Twelve 
months  later  the  blood  (save  for  the  persistence  of  mast  cells)  and 
spleen  were  still  normal.  Other  cases  have  been  recorded  showing 
brief  periods  of  temporary  decline  to  normal  in  the  number  of 
leucocytes,  but  with  the  persistence  of  myelocytes,  or  of  the  splenic 
enlargement,  or  of  both. 

Here  may  be  noted  the  astonishing  results  of  Rontgen-ray 
therapy,  alone  and  in  conjunction  with  arsenic,  in  the  treatment 
of  myelogenous  leukemia.  Senn,2  E.  J.  Brown,3  C.  H.  Weber,4 
Grosh  and  Stone,5  Bryant  and  Crane,6  and  Aubertin  and  Beau- 
jard 7  have  reported  cases  thus  treated,  in  which  the  blood  picture 
became  normal  and  the  splenic  tumor  disappeared.  Time  alone 
can  determine  whether  such  cures  are  symptomatic  or  radical. 

The  following  summary  illustrates  the  good  effects  of  arsenic, 
and,  in  the  patient  in  question,  the  indifferent  results  of  #-ray 
therapy  in  myelogenous  leukemia,  observed  in  the  Jefferson  Hos- 


pital : 

After  Twelve  After  Six  Weeks' 

On  Admission.  Weeks'  Arsenic  Arsenic  Treatment 

Treatment.  with  X-ray. 

Hemoglobin  60  per  cent.  80  percent.  70  percent. 

Erythrocytes  3,520,000  4,860,000  3,090,000 

Leucocytes                            341,000  32,000  147,600 

Small  lymphocytes                3  per  cent.  2.5  percent.  3.0  percent. 

Large  lymphocytes                1   "     "  1.5    "     "  1.4    "  " 

Polynuclear  neutrophiles.  .50  "     "  74.5    "     "  74.9    "  " 

Eosinophiles                        3  "     "  2.0    "     "  3.6    "  " 

Myelocytes  15   "     "  16.0    "     "  10.0    "  " 

Mast  cells  28  "     "  3.5    "     "  7.1    "  " 


The  presence  of  myelocytes  in  large  numbers  is  the  hinge  upon 
which  the  diagnosis  of  myelogenous  leukemia  must  turn,  for  in 

1  Johns  Hopkins  Hosp.  Bull.,  1904,  vol.  xv,  p.  181;  also  Med.  News,  1904,  vol. 
lxxxiv,  p.  431. 

2  Med.  Rec,  1903,  vol.  lxiv,  p.  281. 

3  Jour.  Amer.  Med.  Assoc.,  1904,  vol.  xlii,  p.  827. 

4  Amer.  Med.,  1904,  vol.  vii,  p.  824. 

5  Jour.  Amer.  Med.  Assoc.,  1904,  vol.  xliii,  p.  18. 

6  Med.  Rec,  1904,  vol.  lxv,  p.  574.  7  Presse  med.,  1904,  vol.  i,  p.  399. 


I.KUKKMIA. 


3T3 


no  other  disease  are  these  cells  so  numerous  or  so  constantly 
present.  A  high  percentage  of  myelocytes,  irrespective  of  the 
degree  of  increase  in  the  total  number  of  leucocytes  of  all  forms, 
is  as  essential  for  the  diagnosis  of  this  variety  of  leukemia  as  is  a 
predominance  of  megaloblasts  for  the  recognition  of  pernicious 
anemia.  In  most  cases  they  constitute  at  least  20  per  cent,  of 
the  different  forms  of  leucocytes,  and  occasionally  as  high  as  50 
per  cent,  or  more.  In  the  29  cases  of  the  present  series  (Table 
X)  the  myelocytes,  at  the  first  counts,  averaged  20.6  per  cent., 
with  7  and  44  per  cent,  as  the  minimum  and  maximum  esti- 
mates, respectively.  It  is  the  fact,  not  that  myelocytes  simply 
occur  in  this  disease,  but  that  they  occur  in  such  enormous 
numbers,  that  is  of  prime  value  in  the  diagnosis,  since  in  no  other 
condition  in  which  this  type  of  marrow  leucocyte  is  found  in  the 
blood  are  they  present  in  such  striking  abundance.    For  example, 


12  3  456 

Fig.  53. — Atypical  Forms  of  Myelocytes  in  Myelogenous  Leukemia. 
1,  2,  Dwarf  forms,  with  relatively  large  and  deeply  stained  nuclei  situated  in  a  relatively  small 
amount  of  cell  body  containing  neutrophile  granules.    3.  "Fractured"  myelocyte.     4,  Extremely 
large  form,  with  kidney-shaped  nucleus.    5,  Eosinophilic  myelocyte  with  deeply  constricted  nucleus. 
6,  Myelocyte  with  an  hour-glass  constriction  of  the  nucleus.    (Ehrlich's  triacid  stain.) 


although  myelocytes  are  very  constant  in  pernicious  anemia,  they 
are  only  about  one-twentieth  as  numerous  in  this  disease,  on  the 
average,  as  they  are  in  myelogenous  leukemia. 

Many  of  the  myelocytes  are  of  very  large  size,  some  being 
quite  22  fJL  in  diameter  and  occasionally  of  somewhat  larger  di- 
mensions; others  are  dwarfed  to  no  larger  than  the  diameter  of 
a  small  lymphocyte.  The  nuclei  of  these  larger  forms  stain 
with  relatively  less  intensity  than  those  of  the  smaller.  In- 
dentation, apparent  division,  and  hour-glass  constriction  of  the 
myelocytes'  nuclei  are  also  frequently  noted.  A  very  common 
form  of  this  cell  in  myelogenous  leukemia  is  characterized  by 
its  large  size  and  its  pale,  kidney-shaped  nucleus,  the  regularly 
convex  border  of  which  lies  in  intimate  contact  with  fully  one- 
half  the  periphery  of  the  cell  body.  These  and  other  atypical 
forms  of  myelocytes  are  shown  in  the  accompanying  illustra- 
tion (Fig.  53).    The  abnormalities  affecting  the  granules  of  this 


3*4 


DISEASES  OF  THE  BLOOD. 


type  of  cells,  as  well  as  certain  degenerative  changes,  do  not  differ 
from  those  which  are  found  in  the  polynuclear  neutrophiles 
described  below. 

The  relative  percentage  of  polynuclear  neutrophiles  is  low,  but 
not  especially  so,  although,  of  course,  the  absolute  number  of 
this  type  of  cells  is  greatly  in  excess  of  the  normal  standard,  as 
may  be  demonstrated  by  taking  into  consideration  the  high  total 
leucocyte  count.  For  instance,  in  a  case  having  300,000  leuco- 
cytes per  c.mm.,  with,  say,  50  per  cent,  of  them  polynuclear 
neutrophiles,  the  actual  number  of  the  latter  is  150,000  to  the 
c.mm.,  or  fifteen  times  the  maximum  normal  number.  The 
cases  listed  in  Table  X  averaged  54.3  per  cent,  for  this  variety 
of  leucocytes,  with  a  range  between  34.1  and  77.0  per  cent,  in  the 
individual  case,  but  other  authors,  with  more  extended  series 
of  cases  as  a  basis  for  their  statistics,  give  lower  figures  than  these. 

A  feature  which  at  once  attracts  attention  in  the  examination 
of  the  stained  specimen  is  the  deviation  from  the  normal  size  of 
a  large  proportion  of  these  neutrophilic  cells.  Dwarfed  cells, 
often  not  more  than  5  or  6  p  in  diameter,  and  large  forms,  some 
of  them  measuring  15  p  or  even  more  in  diameter,  are  common, 
the  nuclei  of  the  former  usually  staining  much  more  sharply  than 
those  of  the  latter,  which  may  exhibit  a  very  feeble  reaction  to- 
ward the  basic  dye,  and  show  a  more  diffuse  and  delicate  chro- 
matin structure  than  is  the  rule  in  normal  blood.  The  nuclei 
tend  to  exhibit  extreme  polymorphism  and  variations  in  their 
relative  size  to  that  of  the  cell  body,  and  many  of  the  cells  are 
deformed  in  shape,  being  drawn  out  into  various  oblong  and 
elliptical  designs  or  into  irregular  elongated  masses.  "  Frac- 
tured" cells,  from  which  the  granules  have  escaped,  are  very 
commonly  seen.  It  seems  reasonable  to  attribute  the  free  neu- 
trophil granules  sometimes  seen  in  the  blood  in  this  disease  to 
the  rupture  of  a  neutrophilic  leucocyte,  although  the  particular 
cell  to  which  they  belonged  may  be  difficult  to  identify;  the  view 
expressed  by  some  authors  that  such  granules  may  preexist  in 
the  plasma  is  scarcely  to  be  thought  of  seriously.  All  these 
deformities  are  doubtless  the  result  of  injuries  to  the  cells  in  the 
preparation  of  the  cover-glass  spreads,  and  they  suggest  a  lowered 
resistance  on  the  part  of  the  leucocytes. 

The  number  of  granules  in  the  polynuclear  neutrophiles  varies 
greatly  in  the  individual  cells:  in  some  they  are  densely  crowded 
throughout  the  protoplasm  and  overrun  portions  of  the  nucleus; 
in  others  they  are  confined  to  certain  areas  of  the  cell  body,  es- 
pecially in  the  neighborhood  of  the  nucleus;  while  in  still  others 
they  are  distributed  singly  or  in  twos  and  threes  through  the 


LEUKEMIA. 


315 


protoplasm.  Occasionally  a  cell  wholly  devoid  of  granules  is 
observed,  and,  very  rarely,  one  containing  both  neutrophile  and 
a  few  isolated  eosinophile  or  basophile  granules.  The  neutro- 
phile granules  themselves  vary  greatly  in  size,  being  in  some 
cells  so  extremely  delicate  and  fine  that  they  can  barely  be  dis- 
tinguished, while  in  others  they  almost  equal  the  size  of  the 
smaller  eosinophile  granules. 

Fine  and  coarse  vacuolation  of  the  nucleus  and  protoplasm,  a 
fissured  and  cracked  appearance  of  the  nuclear  chromatin,  and  an 
apparent  solution  of  the  protoplasm,  with  freeing  of  the  nu- 
cleus, are  the  most  prominent  degenerative  changes  affecting  the 
polynuclear  neutrophils,  as  well  as  the  other  varieties  of  leuco- 
cytes, in  this  disease. 

The  relative  percentage  of  lymphocytes,  small  and  large  to- 
gether, is  decidedly  lower  than  normal,  although  their  total  num- 


lit 


1  2  3 

Fig.  54— Atypical  Forms  of  Polynuclear  Neutrophiles  in  Myelogenous  Leukemia. 
1,  Cell  containing  both  neutrophile  and  moderately  coarse  basophile  granules.    2,  Polynuclear 
cell  with  two  ovoid  nuclei  and  neutrophile  granules,  probably  representing  a  later  developmental 
stage  than  6,  Fig.  53.     3,  "Fractured"  polynuclear  neutrophile.     (No.  1  stained  with  Jenner's 
eosinate  of  methylene-blue,  2  and  3  with  Ehrlich's  triacid  stain.) 

ber  to  the  c.mm.  of  blood  is  greatly  increased.  As  shown  by 
the  cases  in  Table  X,  these  cells  average  approximately  14  per 
cent,  of  all  varieties  of  leucocytes,  which  represents  a  diminution 
to  about  one-half  of  the  proportion  found  in  normal  blood.  It 
is  the  small  lymphocytes  which  suffer  the  greater  loss,  for  their 
proportion  in  the  differential  count  is  sometimes  not  more  than 
a  fraction  of  one  per  cent.,  and  always  greatly  below  normal; 
the  large  lymphocytes  and  "  transitional "  forms,  on  the  contrary, 
average  about  normal,  and,  indeed,  may  be  greatly  increased 
in  the  individual  case.  Turk's  stimulation  forms  are  also  met 
with,  but  these  cells,  as  a  rule,  are  not  numerous. 

Atypical  forms  of  lymphocytes  are  not  so  common  in  this  form 
of  leukemia  as  they  are  in  the  lymphatic  variety.  Such  cells  are 
described  under  the  latter  disease.    (See  p.  319.) 

Eosinophilic^,  as  indicated  by  an  increase  in  the  total  number  of 
eosinophiles,  is  almost  invariably  found,  and  an  increase  above 


316 


DISKASKS   OK   THE  MLOOD. 


normal  in  the  relative  percentage  of  these  cells  sometimes,  but  not 
always,  exists.1  Thus,  in  the  above-mentioned  series  the  eosino- 
philes,  which  normally  do  not  exceed  500  per  c.mm.,  ranged 
from  780  to  129,150  and  averaged  14,204  per  c.mm.,  these  figures 
corresponding  to  percentages  of  1.2,  28.7,  and  5.4,  respectively. 

Ehrlich's  original  statement  regarding  an  increase  of  the  eosino- 
philes  in  this  form  of  leukemia  has  been  contradicted  by  several 
writers,  notably  by  von  Limbeck  2  and  by  Miiller  and  Rieder3 ; 
but  these  contradictions  are  based  upon  a  misconception  of  Ehr- 
lich's remarks,  for  he  never  claimed  that  an  abnormally  high 
percentage  of  eosinophiles  was  associated  with  this  disease,  but 
said  simply  that  their  absolute  number  was  increased. 

Marked  variation  in  the  size  of  many  of  the  eosinophiles  is  com- 
monly observed,  dwarf  forms,  5  or  6  fx  in  diameter,  with  densely 
crowded  and  deeply  stained  granules,  being  especially  striking 
and  apparently  more  numerous  than  the  larger  forms.  Eosino- 
philic myelocytes,  differing  from  ordinary  neutrophilic  myelocytes 
only  in  that  they  are  studded  with  eosinophile  granules,  are  very 
numerous,  and  are  among  the  largest  forms  of  the  myelocyte 
found  in  this  disease.  " Fractured"  eosinophiles  are  common, 
being  usually  more  abundant  than  neutrophilic  cells  which  have 
thus  traumatically  suffered.  In  some  of  the  eosinophiles  the 
granules  are  scanty,  and  in  many  their  size  varies  greatly.  Un- 
usually large-sized  granules  are  often  found,  especially  in  the 
dwarf  cells  and  in  the  extremely  large  forms. 

Mast  cells  with  coarse,  metachromatic  granules  are  found 
with  great  constancy,  being  absent  in  but  a  small  proportion  of 
cases.  This  cell  is  especially  suggestive  of  leukemia  of  this 
variety,  since  in  no  other  disease  does  it  occur  in  such  large  num- 
bers. In  19  cases  of  the  above  series  the  mast  cells  averaged 
9  per  cent,  in  the  differential  leucocyte  counts.  In  some 
leukemic  bloods  the  mast  cells  attain  an  enormous  size,  being 
quite  the  largest  cellular  elements  found  in  the  specimen.  They 
may  be  easily  identified  by  their  characteristic  reaction  toward 
the  basic  dyes,  described  in  a  previous  section.    (See  p.  221.) 

From  the  above  remarks  it  may  be  concluded  that  myelocytes 
and  mast  cells  are  present  in  the  circulating  blood  at  the  expense 
of  all  the  normal  varieties  of  leucocytes  except  the  eosinophiles, 
and  that  the  brunt  of  this  decrease  is  sustained  by  the  mono- 
nuclear, non-granular  forms,  chiefly  by  the  small  lymphocytes. 

1  Simon's  case,  in  which  13  differential  counts  were  made,  consistently  showed 
an  absence  of  eosinophiles.    (Amer.  Jour.  Med.  Sci.,  1903,  vol.  cxxv,  p.  984.) 

2  Loc.  cit.  3  Deutsch.  Arch.  f.  klin.  Med.,  189 1,  vol.  xlviii,  p.  96. 


UH1VERS! 


PLATE  V. 


0 


0       .  Q  ±m. 


12 


10 


o : 

Lymphatic  Leukemia. 
(  Triacid  Stain.) 


o 


,     4,  5,  6.  Small  Lymphocytes.  .  . 

These  cells  show  a  great  difference  in  the  intensity  of  their  reaction  toward  the  basic 
dye  The  smallest  forms,  1,2,4,  and  5,  being  richer  in  nuclear  chromatin  and  staining 
more  deeply  than  the  larger,  3  and  6.    Compare  2  with  the  normoblast,  16,  Plate  IV. 

,0,10,11.  Large  Lymphocytes. 

Except  in  10,  which  shows  a  delicate  rim  of  fuehsin-stained  protoplasm,  these  lympho- 
cytes appear  simply  as  pale  chromatin-deficient  nuclear  structures,  lacking  cell  bodies. 
Compare  these  cells  with  the  myelocytes,  Plate  IV. 

Transitional  Form.  .  .  . 

The  upper  edge  of  the  nucleus  is  somewhat  indented  and  the  protoplasm  is  distin- 
guishable; otherwise  this  cell  resembles  a  large  lymphocyte. 


(E.  F.  Faber,  fee.) 


LEUKEMIA. 


These  bodies  are  greatly  increased  in  number 
Blood       in  most  cases  of  this  form  of  leukemia,  and  may 
Plaques.      frequently  be  recognized  in  the  fresh  specimen 
and  in  the  diluted  blood  in  the  counting  chamber 
of  the  hemocytometer.    They  are  very  constantly  observed  in  the 
stained  film  prepared  by  the  Romanowsky  method. 

Lymphatic  Leukemia. 
In  most  cases  the  blood  drop  is  watery-looking, 
Appearance  pale,  and  thin,  for  in  this  variety  of  leukemia  the 
oe  the       anemia  is  usually  very  marked.    The  milky  ap- 
Fresh  Blood,  pearance  of  the  drop,  frequently  observed  in  the 
myelogenous  form  of  the  disease,  is  not  often 
noticed  in  the  lymphatic  variety. 

The  alterations  in  the  coagulability,  alkalinity,  and  specific 
gravity  of  the  whole  blood  are  similar  to  those  met  with  in  mye- 
logenous leukemia. 

Microscopically,  the  field  is  crowded  with  large  numbers  of  leu- 
cocytes, the  vast  majority  of  which  are  mononuclear  cells  encir- 
cled by  a  perfectly  hyaline,  non-granular  protoplasm.  They  may 
be  quite  uniformly  either  of  small  or  of  large  size,  or  so  many  inter- 
mediate sizes  may  be  present  that  it  is  impossible  to  distinguish 
any  single  predominating  type.  It  is  apparent  that  the  leuco- 
cytes do  not  seem  so  numerous  as  in  myelogenous  leukemia, 
nor  are  their  characteristics  so  striking,  at  first  glance,  because  of 
the  lack  of  granulations  in  their  protoplasm.  The  difference 
between  these  hyaline  cells  and  the  granular  leucocytes  of  the 
last-named  disease,  even  although  they  may  not  happen  to  differ 
greatly  in  size  and  shape,  is  at  once  patent  to  the  practised  eye. 
The  changes  affecting  the  size,  color,  and  shape  of  the  eryth- 
rocytes vary  with  the  degree  of  oligochromemia  and  oligocy- 
themia present;  they  are  generally  quite  decided,  as  in  any  high- 
grade  anemia. 

Marked  anemia,  characterized  by' a  dispropor- 
Hemoglobin  tionate  diminution  in  hemoglobin,  is  the  general 
and         rule  in  this  variety  of  leukemia,  the  decrease  in 
Erythrocytes,  both  hemoglobin  and  erythrocytes,  especially  in 
the  former,  being  frequently  greater  than  in  the 
myelogenous  form.    In  a  series  of  13  cases  the  following  figures, 
referring  to  the  initial  examinations,  were  obtained : 


3i8 


DISEASES  OF  THE  BLOOD. 


TABLE  XL— HEMOGLOBIN  AND  ERYTHROCYTES  IN   13   CAS  JOS 
OF  LYMPHATIC  LEUKEMIA. 


Hemoglobin 
Percentage. 


Number  of 
Cases. 


From  40-50  1 

"     3°-4o  4 

"     20-30  4 

"     10-20  4 

Average,      38.1  per  cent. 

Maximum,  47.0  "  " 

Minimum,    14.0  "  " 


Erythrocytes  Number  of 

per  c.mm.  Cases. 

From  3,000,000-4,000,000  3 

"     2,000,000-3,000,000  4 

"     1,000,000-2,000,000  6 


Average, 

Maximum, 

Minimum, 


3,032,211  per  c.mm. 
3,590,000  "  " 
1,152,000  "  " 


In  rare  instances  the  number  of  erythrocytes  falls  below 
1,000,000,  and  the  hemoglobin  so  low  that  it  is  impossible  to 
estimate  the  percentage  at  all  accurately.  Rapidly  developing 
and  extremely  pronounced  anemia  is  generally  observed  in  cases 
which  pursue  an  apute  course. 

Nucleated  erythrocytes,  chiefly  of  the  normoblastic  type,  are 
commonly  found  in  moderate  numbers,  but  never,  except  in  rare 
instances,  usually  occurring  in  children,  are  they  as  numerous 
as  in  the  myelogenous  form  of  the  disease.  As  a  rule,  when 
both  normoblasts  and  megaloblasts  are  present,  the  former  vastly 
outnumber  the  latter,  although  occasionally  one  meets  with  a 
case  in  which  this  predominance  of  adult-type  erythroblasts  is 
less  pronounced.  Thus,  in  one  of  the  writer's  cases  the  total 
number  of  erythroblasts  was  calculated  at  10,678  per  c.mm.,  of 
which  8512  were  normoblasts  and  2166  megaloblasts;  such  a 
blood  picture  as  this,  however,  is  but  seldom  found.  In  general 
terms  it  may  be  said  that  the  more  acute  the  form  of  the  disease, 
the  more  decided  the  oligochromemia  and  oligocythemia,  and  the 
more  abundant  the  erythroblasts,  the  number  and  character  of 
which  appear  to  depend  upon  the  grade  of  the  anemia  present. 
It  should  not  be  forgotten  that  in  some  cases  of  typical  lymphatic 
leukemia  nucleated  erythrocytes  are  so  scanty  that  they  are  detected 
only  after  repeated  examinations. 

Deformities  of  size  and  shape  and  atypical  staining  of  the  eryth- 
rocytes are  marked  in  direct  relation  to  the  severity  of  the  anemia. 

The  number  of  leucocytes  is  largely  increased, 
Leucocytes,  but  usually  much  less  strikingly  so  than  in 
myelogenous  leukemia.  Counts  of  500,000  or 
even  of  1,000,000  cells  have,  it  is  true,  been  reported  by  a  few 
observers,  but  only  as  rare  examples  of  the  extreme  increase  which 
it  is  possible  for  the  leucocytes  to  attain  in  this  condition.  The 
cases  in  Table  XII  illustrate  the  range  of  the  leucocytes  in  this 
variety  of  leukemia. 


LEUKEMIA.  319 

TABLE  XIL— NUMBER  OF  LEUCOCYTES  IN  13  CASES  OF  LYM- 
PHATIC LEUKEMIA. 

Leucocytes  per  c.mm.  Number  of  Cases. 

Above  300,000  2 

From  200,000-300,000  1 

"      150,000-200,000  o 

"      100,000-150,000  4 

"       50,000-100,000  3 

Below   50,000   3 

Average,      270,822  per  c.mm. 

Maximum,  958,000  "  " 

Minimum,     38,000  "  " 

By  examination  of  the  stained  film  the  identity  of  the  leuco- 
cytes responsible  for  the  high  count  is  more  clearly  distinguish- 
able, and  it  is  found  that  the  increase  is  due  to  a  large  absolute 
gain  in  the  lymphocytes,  the  relative  percentage  of  these  cells  to 
the  other  varieties  of  leucocytes  generally  being  90,  95,  or  even 
higher.  In  the  series  below  summarized  (Table  XIII)  these 
non-granular  cells  averaged  89.8  per  cent,  of  the  leucocytes,  and 
equaled  or  exceeded  90  per  cent,  in  three-fourths  of  the  cases 
examined.  In  some  instances  the  small  lymphocytes  are  found 
to  be  in  excess,  and  the  field  is  dotted  with  small,  deeply  stained 
cells  ranging  from  about  5  to  10  p.  in  diameter;  in  other  instances 
the  larger  forms  prevail,  so  that  large,  feebly  stained  cells,  from 
about  10  to  15  fJ-  or  even  larger,  are  in  excess;  while  in  still  other 
cases  the  sizes  and  staining  properties  of  the  cells  are  so  variable 
and  atypical  that  it  is  impracticable  to  class  them  in  two  definite 
groups,  large  and  small.  It  is  generally  believed  that  small 
lymphocytes  are  associated  with  the  more  chronic  forms  of  the  dis- 
ease, and  that  the  larger  varieties  are  found  in  excess  in  the  acute 
cases.  Many  of  the  larger  forms,  which  possess  a  relatively  large 
nucleus  deficient  in  chromatin  and  a  faintly  basic  non-granular 
protoplasm,  are  regarded  as  the  mother-cells  of  the  typical  small 
lymphocytes.  They  are  identical  with  the  "  lymphogonien "  of 
Benda  and  the  "  leukoblasts "  of  Lowit,  cells  resident  in  the  ger- 
minal nests  of  the  lymphatic  tissues. 

TABLE  XIII.— QUALITATIVE  CHANGES  IN  THE  LEUCOCYTES  IN 
13  CASES  OF  LYMPHATIC  LEUKEMIA. 

Average.  Maximum.  Minimum. 

Total  lymphocytes  89.8  97.7  53.0 

Small  lymphocytes  51.4  94.0  21. 1 

Large  lymphocytes  38.4  76.2  1.0 

Polynuclear  neutrophils      .  7.6  45.0  1.6 

Eosinophiles    0.6  5.0  0.1 

Myelocytes    1.4  4.9  0.3 

Mast  cells  1   0.1  1.0  0.0 


Estimates  in  6  cases. 


320 


DISEASES  OF  THE  BLOOD. 


Various  atypical  forms  of  lymphocytes,  the  commonest  of 
which  are  pictured  below  (Fig.  55),  are  often  numerous.  With 
basic  stains,  such  as  methylene-blue,  a  ragged,  torn  condition 
of  the  basic  seam  of  protoplasm,  with  so-called  "budding,"  is 
frequently  demonstrable,  as  well  as  nucleolation  of  some  cells, 
especially  of  those  of  large  size.  Nuclear  indentation  and  division 
and  forms  characterized  by  a  small  lymphocyte's  nucleus  within 
a  large  lymphocyte's  cell  body  are  also  common. 

The  relative  proportion  of  polynuclear  neutrophiles  is  markedly 
diminished,  commonly  to  from  about  5  or  10  per  cent,  of  the 
total  number  of  leucocytes,  and  sometimes  even  to  below  one  per 
cent.  These  cells  do  not  usually  display  the  abnormal  staining, 
the  nuclear  peculiarities,  and  the  irregularities  in  size  and  shape 
that  are  so  often  seen  in  myelogenous  leukemia. 

Myelocytes  are  present  in  the  great  majority  of  cases,  but  al- 
ways in  trifling  numbers,  as  in  pernicious  anemia;  their  propor- 
tion rarely  exceeds  one  or  two  per  cent,  of  all  forms  of  leucocytes. 


1  2  3456 

Fig.  55. — Atypical  Forms  of  Lymphocytes  in  Lymphatic  Leukemia. 
1,  Large  lymphocyte  with  ragged  protoplasm.  Two  small  bits  of  protoplasm,  the  product  of 
"budding,"  lie  free  in  the  plasma  beside  the  cell.  2,  Large  lymphocyte  showing  a  nucleolus.  3, 
Large  lymphocyte  containing  two  nuclei.  4,  Small  lymphocyte  containing  an  indented  nucleus.  5, 
Small  lymphocyte  containing  two  nuclei.  6,  Cell  the  size  of  a  large  lymphocyte  with  the  nucleus  of 
a  small  lymphocyte.  (1  and  2  are  stained  with  eosin  and  methylene-blue;  3,  4,  5,  and  6  with 
Ehrlich's  triacid  stain.) 

The  percentage  of  eosinophiles  is  diminished,  usually  to  a  frac- 
tion of  one  per  cent.,  and  in  a  certain  proportion  of  cases  these  cells 
are  absent  from  the  peripheral  blood.  It  must  be  remembered, 
however,  that  even  with  a  low  relative  percentage  figure  for  the 
eosinophiles  true  eosinophilia  may  exist,  although  usually  not  to 
so  marked  a  degree  as  in  the  myelogenous  form  of  the  disease. 
One  per  cent,  of  eosinophiles  in  a  leucocyte  count  of  100,000  means 
1000  eosinophiles  per  c.mm.  of  blood,  or  twice  the  maximum  num- 
ber found  in  the  normal  individual.  Eosinophilic  myelocytes  are 
rare,  but  they  occur  in  small  numbers  in  an  occasional  case. 

Increase  in  the  number  of  basophiles  does  not  occur  with  great 
frequency,  and  both  the  finely  granular  basophilic  leucocytes  and 
the  typical  mast  cells  are  generally  conspicuous  by  their  absence, 
in  contrast  to  their  abundance  in  the  myelogenous  variety  of  this 
disease. 


LKUkiairA. 


321 


From  the  above  it  is  evident  that  in  lymphatic  leukemia  the 
increase  in  the  total  number  of  leucocytes  is  dependent  upon  a 
marked  absolute  gain  in  the  lymphocytes,  and  that  in  conse- 
quence of  this  enormous  influx  of  mononuclear  hyaline  forms, 
the  relative  percentages  of  the  other  leucocytes,  especially  of  the 
polynuclear  neutrophilcs,  are  correspondingly  diminished. 

As  in  the  myelogenous  form,  the  number  of  blood  plaques  is 
usually  much  increased. 

This  term  has  been  applied  to  a  form  of  leu- 
Acute       kemia  which  pursues  a  rapid  course  suggestive 
Leukemia,    of  an  acute  infectious  process,  and  ends  fatally 
within  a  few  weeks  after  the  onset  of  the  acute 
symptoms.    Rapid,  progressive  enlargement  of  the  lymphatic 
glands  and  a  relatively  small  splenic  tumor,  associated  with  such 
clinical  features  as  rigors  and  irregular  pyrexia,  bone  pains,  ulcer- 
ative stomatitis,  and  a  decided  tendency  to  purpura  and  to  hemor- 
rhages from  the  mucous  membranes,  serve  to  identify  most  cases 
of  this  rapidly  fatal  disease.    But,  as  already  stated,  there  may 
be  no  evidences  of  lymphatic  or  splenic  involvement,  the  lesions 
in  such  cases  being  confined  to  the  bone  marrow  or  to  the  deep 
lymph  nodes.    Some  authors  limit  the  duration  of  acute  leukemia 
to  six  weeks,  but  the  time  limit  proposed  by  Fraenkel,1  four  months, 
is  generally  accepted  as  being  more  appropriate. 

The  disease  is  a  rare  one,  for  probably  less  than  100  authentic 
cases  have  been  recorded  up  to  the  present  time,  although  many 
more  reputed  instances  have  been  published.  Ebstein2  collected 
17  cases  in  1889;  Fraenkel3  published  the  statistics  of  10  in  1895; 
Bradford  and  Shaw4  described,  in  1898,  5  cases  coming  under  their 
observation;  and  Fussell,  Jopson  and  Taylor,5  in  the  same  year, 
published  a  collective  report,  embracing  the  statistics  of  57  cases 
selected  as  representing  all  the  true  examples  of  acute  leukemia 
reported  during  the  past  twenty-one  years.  Since  this  report 
about  30  additional  cases  have  been  described  by  various  observers.6 

Beyond  stating  that  lymphemia  is  the  type  of  blood  character- 
istic of  acute  leukemia,  no  special  description  of  the  condition  of 
the  blood  is  necessary.  In  the  majority  of  cases  the  leucocyte 
increase  may  be  attributed  to  a  marked  gain  in  the  large  lympho- 

1  Deutsch.  med.  Wochenschr.,  1895,  vol.  xxi,  p.  639,  et  seq. 

2  Deutsch.  Arch.  f.  klin.  Med.,  1889,  vol.  xliv,  p.  343.  3  Loc.  cit. 

4  Medico-Chirurg.  Trans.,  London,  1898,  vol.  lxxxi,  p.  343. 

5  Trans.  Assoc.  Amer.  Phys.,  Philadelphia,  1898,  vol.  xiii,  p.  124. 

6  For  a  review  of  the  literature  of  acute  leukemia  see  (1)  Hamman,  Amer.  Med., 
1904,  vol.  vii,  p.  138;  (2)  Kelly,  Univ.  of  Penna.  Bull.,  1903,  vol.  xvi,  p.  270;  (3) 
Miller  and  Hess,  Amer.  Med.,  1904,  vol.  vii,  p.  389;  (4)  Mixa,  Wien.  klin.  Rund- 
schau, 1901,  vol.  xv,  pp.  655  and  671;  (5)  Billings  and  Capps,  Amer.  Jour.  Med. 
Sci.,  1903,  vol.  cxxvi,  p.  375. 


322 


DISEASES  OF  THE  BLOOD. 


cytes,  which  greatly  predominate  over  the  small  forms,  while  the 
polynuclear  neutrophiles,  myelocytes,  and  eosinophils  are  rela- 
tively few  in  number.  As  a  rule,  the  more  acute  the  case,  the 
more  decided  the  predominance  of  the  large  lymphocytes,  which 
usually  show  well-marked  evidences  of  nuclear  and  protoplasmic 
degenerative  changes.  The  loss  of  hemoglobin  and  erythrocytes 
is  generally  more  marked  and  the  erythroblasts  are  more  numer- 
ous, than  in  the  commoner  forms  of  chronic  lymphatic  leukemia. 
The  blood  may  coagulate  very  imperfectly  and  the  plaques  are 
often  greatly  diminished  in  number.  In  a  case  reported  by 
Bensaude,1  total  absence  of  clotting  and  of  serum  transudation 
was  noted  after  the  expiration  of  twenty-four  hours. 

Acute  leukemia  may  begin  as  such,  or  either  the  chronic  lym- 
phatic or  the  myelogenous  form  may  develop  acute  symptoms, 
with  a  coincident  change  in  the  condition  of  the  blood,  but  this 
change  in  the  myelogenous  variety  is  extremely  rare.  Only  nine 
cases  of  acute  myelogenous  leukemia  are  on  record.2 

The  development  of  an  acute  infectious  proc- 
Influence  of  ess  in  a  leukemic  individual  commonly  provokes 
Acute  Inter-  striking  changes  in  the  behavior  of  the  leucocytes, 
current  In-   consisting  in  most  instances  in  a  decrease  of  their 
fections.     total  number  to  the  c.mm.  of  blood,  associated 
sometimes  with  an  increase  in  the  polynuclear 
variety  of  cells  and  a  relative  diminution  in  the  number  of  myel- 
ocytes.   At  other  times  there  is  practically  no  alteration  in  the 
relative  proportions  of  the  different  forms  as  they  existed  in  the 
leukemic  blood  prior  to  the  onset  of  the  complicating  infection. 

Among  the  infectious  conditions  acting  in  this  manner  on  the 
leucocytes  are  abscess,  sepsis,  pneumonia,  influenza,  tuberculosis, 
and  erysipelas,  but  it  seems  that  rheumatic  fever  has  no  such  effect. 
Weil,3  who  has  studied  the  effects  of  colon,  pneumococcus,  and 
streptococcus  infections  in  both  forms  of  leukemia,  comes  to  the 
conclusion  that  the  most  powerful  influence  upon  the  blood  pic- 
ture is  exerted  by  streptococcus  infections.  Malignant  disease 
is  also  capable  of  bringing  about  a  leucocyte  decrease  characterized 
by  a  relative  gain  in  polynuclear  neutrophiles  at  the  expense  of 
the  lymphocytes,  but  the  loss  does  not  appear  to  be  so  decided  as 
that  excited  by  a  specific  infectious  process. 

In  rare  instances  the  occurrence  of  an  infectious  disease  fails  to 
cause  a  decrease  in  the  leucocytes,  and  thus  to  destroy  the  leu- 
kemic picture,  but,  on  the  contrary,  increases  them,  by  superim- 

1  Sem.  med.,  1903,  vol.  xxiii,  p.  57. 

2  Billings  and  Capps,  loc.  cit. 

3  Gaz.  hebdom.  de  med.  et  de  chir.,  1900,  vol.  v,  p.  829. 


LEUKEMIA. 


323 


posing  a  typical  polynuclear  ncutrophile  leucocytosis,  which  re- 
mains during  the  existence  of  the  complicating  infection  the 
conspicuous  feature  of  the  blood.  The  writer  has  observed  a 
typical  illustration  of  such  a  change  in  a  case  of  myelogenous 
leukemia,  in  which,  within  ten  days  after  the  onset  of  a  complicat- 
ing peritonitis,  the  leucocyte  count  rose  from  245,000  to  400,000, 
and  the  proportion  of  polynuclear  neutrophiles  from  44.5  to  79 
per  cent.,  while  the  percentage  of  myelocytes  fell  from  20.5 
to  8. 

Dock1  has  collected  50  cases  of  leukemia  complicated  by 
various  intercurrent  infections,  which  in  27  instances  were,  tuber- 
culous and  in  23  non-tuberculous.  In  leukemia  plus  tuberculosis 
the  virulence  of  the  complicating  infection  appears  to  govern  the 
behavior  of  the  leucocytes,  which  are  not  decidedly  influenced 
in  chronic  forms  of  the  disease,  but  which  usually  are  greatly 
diminished  in  the  acute  miliary  type.  In  the  23  cases  of  inter- 
current infections  other  than  tuberculosis  Dock's  analysis  shows 
that  a  marked  leucocyte  decrease  occurred  in  11,  a  relatively 
slight  decrease  in  9,  and  either  an  increase  or  no  change  in  the 
remaining  3.  Of  qualitative  changes  in  these  cases  there  was 
noted  a  general  tendency  of  the  leucocytic  blood  picture  to  dis- 
appear, with  a  decided  increase,  both  absolutely  and  relatively, 
in  the  polynuclear  neutrophiles.  Dock's  masterly  monograph 
should  be  consulted  for  a  complete  account  of  this  complicated 
topic,  which  does  not  lend  itself  to  text-book  discussion. 

Coincidentally  with  the  improvement  in  the  condition  of  the 
blood  there  is  frequently  a  decrease  in  the  size  of  the  patient's  en- 
larged spleen  and  lymphatics,  the  period  during  which  the  leukemic 
condition  is  thus  bettered,  and,  so  to  speak,  held  in  abeyance, 
corresponding  to  the  duration  of  the  complicating  infection,  for 
the  blood  gradually  regains  its  leukemic  type  and  the  glandular 
and  splenic  tumors  reappear  as  recovery  from  the  intercurrent 
disease  takes  place. 

Diagnosis  ^owmS  blood  picture  is  characteristic 

of  the  myelogenous  variety  of  leukemia : 
Hemoglobin.      Decided  loss,  averaging  about  50  per  cent.  Color 

index  subnormal,  or  high. 
Erythrocytes.      Counts    average    about    3,000,000   per  c.mm. 

Erythroblasts  very  numerous,  cells  of  the  normo- 
blastic type  predominating. 

Deformities  of  size  and  shape,  polychromato- 
philia,  and  basophilic  stroma  degeneration  marked 
in  cases  with  severe  anemia. 

1  Amer.  Jour.  Med.  Sci.,  1904,  vol.  cxxvii,  p.  563. 


324 


DISKASKS   OK   T 1 1  I.C  BLOOD. 


Leucocytes.        Increased  to  about  350,000  per  c.mm. 

Myelocytes  constitute  about  20  per  cent,  of  all 
forms. 

Relative  percentage  of  polynuclear  neutrophiles 
low. 

Relative  percentage  of  lymphocytes  very  low. 
Eosinophiles  absolutely,  sometimes  relatively,  in- 
creased. 

Mast  cells  average  about  10  per  cent,  of  all  forms. 

Atypical  forms  of  neutrophiles  numerous. 
Plaques.  Increased. 

In  lymphatic  leukemia  the  blood  changes  may  be  briefly  ex- 
pressed thus : 

Hemoglobin.      Marked  loss,  averaging  about  60  per  cent.  Color 
index  low. 

Erythrocytes.      Counts  average  about  3,000,000  per  c.mm. 

Erythroblasts  usually  scanty,  cells  of  the  normo- 
blastic type  predominating. 
Deformities  of  size  and  shape  and  atypical  stain- 
ing reaction  marked  in  relation  to  the  degree  of 
anemia  present. 

Leucocytes.        Increased  to  about  250,000  per  c.mm.,  counts 
above  this  figure  being  rare. 
Lymphocytes  constitute  about  90  per  cent,  of  all 
forms. 

Relative  percentage  of  polynuclear  neutrophiles 
strikingly  low. 

Relative  percentage  of  eosinophiles  diminished; 

rarely,  an  absolute  increase. 

Small  numbers  of  myelocytes  frequent. 

Basophiles  usually  not  increased. 

Atypical  forms  of  lymphocytes  numerous. 
Plaques.  Increased. 

In  dealing  with  the  differential  diagnosis  of  leukemia  it  is  nec- 
essary to  distinguish  the  myelogenous  from  the  lymphatic  form, 
and  also  to  differentiate  both  forms  of  the  disease  from  a  number 
of  other  conditions  which  may  present  either  somewhat  similar 
blood  findings  or  which,  apart  from  the  condition  of  the  blood, 
may  have  closely  similar  clinical  manifestations.  Thus,  on  the 
one  hand,  leucocytosis  and  lymphocytosis  require  differentiation 
because  they  produce  changes  in  the  blood  which  may  be  con- 
fused with  leukemia;  while,  on  the  other  hand,  one  must  dis- 
tinguish between  leukemia  and  Hodgkin's  disease,  splenic  anemia, 
and  a  number  of  conditions  causing  enlargement  of  the  spleen, 


LEUKEMIA. 


325 


neighboring  organs,  and  lymphatic  glands,  because  of  the  resem- 
blance, even  the  identity  in  some  instances,  of  the  other  clinical 
signs. 

Myelogenous  and  lymphatic  leukemia  can  be  distinguished 
only  by  examination  of  the  blood,  for  the  distinction  between 
these  two  forms  of  the  disease  cannot  be  based  with  any  degree 
of  certainty  upon  the  gross  clinical  appearance  of  the  spleen  a*nd 
lymphatics.  Nothing  can  be  more  marked  than  the  contrast  be- 
tween the  two  blood  pictures.  In  the  myelogenous  form  the 
leucocyte  count  is  usually  much  higher,  and  is  associated  with  the 
presence  of  immense  numbers  of  myelocytes,  and  with  an  increase 
in  the  eosinophiles  and  mast  cells;  the  oligocythemia  is  not  so 
marked,  but  erythroblasts  are  exceedingly  numerous,  and,  strangely, 
tend  to  persist  independently  of  any  increase  in  the  erythrocytes 
which  may  occur  from  time  to  time.  In  the  lymphatic  form 
the  relatively  moderate  leucocyte  increase  depends  upon  an 
excessive  gain  in  the  ungranulated  cells,  or  lymphocytes,  myelo- 
cytes being  either  absent  or  present  in  trifling  numbers,  and 
decided  increase  in  the  eosinophiles  and  mast  cells  being  most 
unusual;  the  oligocythemia  is  usually  decided,  but  erythroblasts 
are  scanty,  and  stand  in  relationship  to  the  degree  of  anemia 
existing.  The  important  points  of  difference  are,  therefore,  the 
presence  of  a  myelocytic  blood  in  the  myelogenous  form,  and  of 
a  lymphocytic  blood  in  the  lymphatic  variety. 

Pathological  leucocytosis  may  occasionally  involve  an  increase 
in  the  total  number  of  leucocytes  equal  to  that  found  in  either 
form  of  leukemia,  especially  in  those  cases  in  which  a  period 
of  temporary  improvement  with  a  fall  in  the  leucocyte  count 
exists.  But,  aside  from  the  more  or  less  temporary  character  of 
the  increase  in  leucocytes,  the  differential  count  at  once  shows 
that,  unlike  leukemia,  the  gain  depends  upon  a  large  absolute  and 
relative  increase  in  the  polynuclear  neutrophiles,  which  constitute 
ordinarily  85  per  cent,  or  more  of  the  several  forms  of  leucocytes. 

Lymphocytosis,  which  is  usually  a  relative  condition,  may  in 
rare  instances  become  absolute,  so  that,  in  addition  to  the  increase  in 
the  relative  percentage  of  lymphocytes,  the  total  number  of  leu- 
cocytes in  the  blood  is  also  decidedly  increased.  In  marked  in- 
stances of  this  sort  it  is  obviously  impossible  to  distinguish  the 
blood  change  from  that  of  lymphatic  leukemia,  and  the  aid  of 
other  clinical  symptoms  must  be  invoked  to  make  the  diagnosis 
clear.  Thus,  both  an  absolute  and  a-  relative  lymphocytosis, 
closely  simulating  the  lymphatic  form  of  leukemia,  have  been 
observed  in  severe  cases  of  chlorosis,  in  pertussis,  in  sarcoma  of  the 
lymphatic  structures,  and  in  acute  inflammatory  processes  oc- 


326 


DISEASES  OF  THE  BLOOD. 


curring  in  young  children.  The  author  recalls  an  instance  of 
marked  absolute  lymphocytosis  in  a  case  of  pernicious  anemia 
which  seemed  to  justify  the  tentative  diagnosis  of  lymphatic  leu- 
kemia, an  error  which  was  later  corrected,  when  the  megaloblastic 
blood  picture  became  apparent.  In  such  instances,  which  are, 
fortunately,  of  very  rare  occurrence,  it  is  true  that  neither  the  per- 
centage of  lymphocytes  nor  the  count  of  leucocytes  is  likely  to 
average  so  high  as  in  lymphatic  leukemia,  but  still  the  blood 
changes  are  sometimes  very  misleading,  and  should  not  be  relied 
upon  to  the  exclusion  of  other  equally  important  symptoms. 

The  glandular  and  splenic  enlargements  of  Hodgkin's  disease 
form  a  clinical  picture  identical  with  either  the  myelogenous  or 
the  lymphatic  variety  of  leukemia,  so  that  these  conditions  are 
distinguishable  only  by  the  result  of  the  blood  examination.  But 
by  this  means  the  diagnosis  is  made  extremely  simple,  by  finding 
in  Hodgkin's  disease  either  entirely  normal  blood  or  a  variable 
degree  of  anemia.  The  number  of  leucocytes  is  usually  nor- 
mal, except  in  cases  in  which  some  complicating  inflammatory 
or  infectious  process  causes  a  moderate  increase,  typical  of  a 
polynuclear  neutrophile  leucocytosis. 

In  chloroma  the  blood  changes  may  be  practically  those  of 
an  acute  lymphatic  leukemia — progressive  anemia  with  absolute 
lymphocytosis.  In  chloroma,  however,  the  clinical  picture  is 
made  up  of  exophthalmos,  deafness,  orbital  pain,  elastic  swellings 
of  the  orbital  and  temporal  regions,  and  a  tendency  toward  met- 
astases of  the  "green  tumors"  in  periosteal  structures. 

Von  Jaksch's  multiple  periostitis  is  a  symptom-complex 
resembling  myelogenous  leukemia,  in  that  a  myelocytic  anemia 
with  splenic  enlargement  and  a  tendency  toward  hemorrhage  are 
symptoms  common  to  both  conditions.  In  the  early  stages  of  the 
disease  described  by  von  Jaksch,  fever,  drenching  sweats,  painful 
and  swollen  joints,  and  thickening  of  the  distal  extremities  of  the 
radius  and  ulna  are  observed,  these  distinctive  symptoms  being 
succeeded  by  a  preagonal  stage  marked  by  a  cessation  of  the  bone 
pains  and  sweating  and  by  an  aggravation  of  the  already  marked 
anemia,  splenomegaly,  and  hemorrhagic  tendency. 

StilVs  disease,  because  of  the  splenic  and  lymph-node  enlarge- 
ments, may  superficially  resemble  leukemia,  but  in  this  form  of 
infantile  arthritis,  besides  an  aleukemic  blood  picture,  one  finds 
multiple  arthritis,  especially  of  the  periarticular  structures,  and 
usually  a  clear  history  of  rickets. 

The  rather  close  resemblance  which  certain  cases  of  splenic 
anemia  bear  to  leukemia,  together  with  the  points  of  difference 
between  them,  have  already  been  described.    (See  p.  295.) 


hodgkin's  disease. 


327 


Enlargements  of  the  s pleen,  left  kidney,  and  pancreas  may  lead 
to  the  belief  that  leukemia  exists.  Thus,  splenie  tumors  due 
to  chronic  malarial  infection,  to  amyloid  disease,  to  cysts,  and  to 
malignant  neoplasms;  enlargements  of  the  left  kidney,  such  as 
can  be  caused  by  hydronephrosis,  by  cysts,  and  by  malignant 
disease;  as  well  as  cystic  tumors  of  the  pancreas  and  malignant 
disease  of  the  retroperitoneal  glands  all  may,  on  physical  exami- 
nation, simulate  more  or  less  faithfully  the  leukemic  spleen.  The 
negative  character  of  the  blood  findings  will  at  once  exclude  leu- 
kemia, should  one  of  the  above-named  conditions  be  the  cause 
of  the  physical  signs  suggesting  this  disease. 

Lymphatic  hyperplasia,  due  to  tuberculosis,  to  syphilis,  and  to 
malignant  disease,  may  also  be  mistaken  for  the  glandular  in- 
volvement of  leukemia,  for  such  enlargements  sometimes  show 
nothing  distinctive.  In  tuberculous  adenitis  the  blood  is  either 
normal  or  anemic,  if  the  cachectic  state  of  the  patient  is  marked; 
or,  should  there  happen  to  be  a  secondary  infection  of  the  glands 
plus  the  tuberculous  lesions,  a  simple  polynuclear  leucocytosis 
is  found.  In  syphilitic  adenitis  there  is  often  anemia  with  a  mod- 
erate polynuclear  leucocytosis,  and  sometimes  with  a  relative 
lymphocytosis,  especially  in  children.  In  malignant  disease  of 
the  lymphatics  increase  in  the  number  of  leucocytes  may  also  be 
noted  in  association  with  a  high-grade  anemia;  in  carcinoma  the 
increase  involves  chiefly  the  polynuclear  neutrophiles,  but  in  sar- 
coma the  lymphocytes  may  be  unduly  increased,  though  not  to 
the  extent  found  in  lymphatic  leukemia. 

VII.  HODGKIN'S  DISEASE. 

Nothing  characteristic  is  observed  either  in 
Appearance  the  gross  appearance  of  the  fresh  blood  drop  or  in 
of  the       the  unstained  film,  microscopically.    The  blood 
Fresh  Blood,  may  appear  normal,  or  it  may  show  changes 
common  to  any  secondary  anemia. 
The  alkalinity  and  specific  gravity  of  the  whole  blood  are  di- 
minished in  relation  to  the  degree  of  anemia  which  exists.  Coag- 
ulation may  take  place  slowly,  and  even  be  as  incomplete  as  it 
is  in  some  cases  of  leukemia;  or  it  may  occur  within  the  normal 
time  limit. 

Both   the  hemoglobin  percentage  and  the 
Hemoglobin  number  of  erythrocytes  are  normal  in  the  early 
and         stages  of  the  disease,  and  in  slowly  progressive 
Erythrocytes,  cases  the  blood  may  remain  unaffected  for  a  long 
period.    But  sooner  or  later,  as  the  disease  pro- 


328 


DISEASES  OF  THE  BLOOD. 


grosses  and  a  cachectic  condition  of  the  patient  develops,  anemia 
appears,  gradually  where  the  course  of  the  disorder  is  slow,  and 
rapidly  in  the  more  acute  forms.  Counts  made  when  the  patient 
first  comes  under  observation  usually  average '  4,000,000  or  5,000,- 
000  cells  per  c.mm.,  but  in  the  later  stages  the  number  frequently 
falls  to  one-half  this  figure  or  even  less.  The  loss  of  hemoglobin 
begins  earlier,  and  in  most  instances  is  proportionately  somewhat 
greater,  than  the  erythrocyte  decrease,  so  that  subnormal  color 
indices  rule — not  decidedly  low,  but  yet  twenty  points  or  so  below 
the  normal  standard.  In  cases  which  develop  excessive  oligocy- 
themia the  index  figures  may  be  quite  as  high  as  in  pernicious 
anemia. 

In  the  series  of  21  cases  summarized  in  Table  XIV,  the  hemo- 
globin averaged  about  55  per  cent.,  ranging  between  30  and  81 
per  cent.;  the  erythrocyte  count  averaged  3,591,423  per  c.mm., 
the  minimum  being  1,300,000  and  the  maximum  5,225,000,  with 
more  than  one-third  of  the  cases  having  4,000,000  cells  or  more. 


TABLE  XIV.— HEMOGLOBIN  AND  ERYTHROCYTES  IN  21  CASES 
OF  HODGKIN'S  DISEASE. 

Hemoglobin.  Number  of         Erythrocytes  Number  oe 

Percentage.  Cases.  per  c.mm.  Cases. 

From  80-90  3  Above  5,000,000   2 

"     70-80  3  From  4,000,000-5,000,000   6 

"     60-70  1  "     3,000,000-4,000,000  10 

"     50-60  6  "     2,000,000-3,000,000   1 

"     4°-5°  4  "     1,000,000-2,000,000   2 

"     3°-40  4 

Average,      55.3  per  cent.  Average,      3,591,423  per  c.mm. 

Maximum,  81.0  "      "  Maximum,  5,225,000  "  " 

Minimum,    30.0  "      "  Minimum,    1,300,000  "  " 

Qualitative  changes  affecting  the  corpuscles  occur  in  relation 
to  the  intensity -of  the  anemic  process,  deformities  of  shape  and 
size  and  atypical  staining  reaction  of  the  cells  being  associated 
with  cases  in  which  notable  hemoglobin  and  erythrocyte  losses 
exist,  and  being  absent  when  the  anemia  is  moderate.  Nucle- 
ated erythrocytes  are  not  common,  nor  are  they  numerous  when 
present.  Usually  they  are  wanting,  except  in  connection  with  a 
high-grade  anemia,  under  which  circumstance  a  few  normoblasts 
may  be  detected,  and  in  rare  instances  an  occasional  megaloblast. 

In  the  average  case  the  leucocytes  are  normal, 
Leucocytes,  both  in  number  and  in  the  relative  percentage  of 
different  varieties.    More  rarely,  relative  lym- 
phocytosis occurs,  involving  a  decrease  in  the  percentage  of  poly- 
nuclear  neutrophiles,  but  not  increasing  the  total  number  of 
leucocytes.    An  instance  of  this  kind  has  been  observed  by  the 


hoixikin's  DISK  ASM. 


329 


writer,  in  which  the  relative  proportion  of  lymphocytes  to  other 
forms  of  leucocytes  habitually  remained  for  some  months  between 
70  and  85  per  cent;,  this  change  affecting  chiefly  the  large  lym- 
phocytes, while  the  total  leucocyte  count  never  exceeded  normal. 

TABLE  XV.— NUMBER  OF  LEUCOCYTES  IN  21  CASES  OF  HODG- 
KIN'S  DISEASE. 

Leucocytes  per  c.mm.  Number  of  Cases. 

Above  20,000  1 

From  15,000-20,000  3 

"      10,000-15,000  4 

"       5,000-10,000  7 

Below   5,000  6 

Average,       8,819  Per  c.mm. 

Maximum,  21,000  "  " 

Minimum,     1,000  "  " 

If  secondary  infection  takes  place,  it  soon  becomes  evident  by 
an  increase  in  the  leucocytes  to  about  20,000  or  more,  principally 
involving  the  polynuclear  neutrophile  cells,  at  the  expense  of  the 
lymphocytes — a  picture  of  typical  leucocytosis.  In  some  in- 
stances, however,  without  any  apparent  signs  of  a  secondary  in- 
fection or  of  a  glandular  inflammation,  the  total  count  may  ex- 
ceed the  normal  standard  by  several  thousand  cells,  and  yet  show 
a  normal  or  even  somewhat  decreased  proportion  of  neutrophiles. 
These  changes  in  the  blood  picture  must  be  distinguished  from 
those  indicating  the  conversion  of  Hodgkin's  disease  into  true 
lymphatic  leukemia.  This  transition,  although  exceedingly  rare, 
probably  sometimes  occurs,  as  shown  by  Wende,1  Posselt,2 
Senator,3  Mosler,4  Fleischer  and  Penzoldt,5  and  others.  Should 
the  anemia  be  very  marked,  pronounced  leucopenia  is  commonly 
associated  with  it.  In  the  present  series  (Table  XV)  about  one- 
fourth  of  the  cases  showed  frank  leucocytosis,  the  highest  estimate 
being  21,000,  the  lowest  1000,  and  the  average  8819. 

TABLE  XVI.— QUALITATIVE  CHANGES  IN  THE  LEUCOCYTES  IN 
21  CASES  OF  HODGKIN'S  DISEASE. 

Average.               Maximum.  Minimum. 

Small  lymphocytes  16.5                    49.0  1.0 

Large  lymphocytes  10.8                    21.0  0.5 

Polynuclear  neutrophiles  ...69.6                    88.0  46.2 

Eosinophils                           2.2                    10. o  0.0 

Myelocytes                             0.5                      3.0  0.0 

Mast  cells  6                             0.9                      1.1  0.0 

1  Amer.  Jour.  Med.  Sci.,  1901,  vol.  cxxii,  p.  836. 

2  Wien.  klin.  Wochenschr.,  1895,  vol.  viii,  p.  407. 

3  Berlin,  klin.  Wochenschr.,  1882,  vol.  xix,  p.  533. 

4  Vir chow's  Arch.,  1888,  vol.  cxiv,  p.  461. 

5  Deutsch.  Arch.  f.  klin.  Med.,  1896,  vol.  lxvii,  p.  300. 

6  Estimates  in  11  cases. 


33° 


MSKASKS   OF  THE  BLOOD. 


Small  numbers  of  myelocytes  are  not  uncommon  in  the  ad- 
vanced anemia  of  Hodgkin's  disease,  but  they  are  never  more 
numerous  than  in  any  other  condition  accompanied  by  a  similar 
deterioration  of  the  blood.  These  cells  were  found  in  8  of  the  21 
cases  under  consideration. 

Small  numbers  and  low  percentages  of  eosinophiles  are  the 
rule,  in  cases  both  with  and  without  leucocytosis ;  it  is  most  un- 
usual for  these  cells  to  attain  the  maximum  normal  figure,  and 
they  are  sometimes  wholly  absent. 

Neither  the  finely  granular  basophiles  nor  the  typical  mast  cells 
are  increased  in  this  disease.  The  author  found  the  latter  in  but 
a  single  case  of  11  examined. 

As  in  both  forms  of  leukemia,  the  number  of  blood  plaques  in 
Hodgkin's  disease  is  usually  increased. 

;  Although  no   characteristic  blood  changes 
Diagnosis,    occur  in  this  condition,  the  alterations  most  com- 


monly observed  may  be  briefly  summed  up  as 
follows : 


Hemoglobin.      Normal  in  the  early  stages  of  the  disease ;  later,  a 


moderate  decrease,  estimates  averaging  about  55 
per  cent.  Color  index  commonly  subnormal^ 
rarely  high. 


Erythrocytes.      Normal  in  the  early  stages ;  later,  a  variable  degree 


of  oligocythemia,  counts  averaging  about  3,500,- 
000  per  c.mm. 

Erythroblasts  uncommon  and  scanty  when  pres- 
ent. 

Normoblasts  prevail  almost  exclusively,  megalo- 
blasts  being  very  rare. 

Deformities  of  size  and  shape,  polychromato- 
philia,  and  basic  stroma  degeneration  only  in  cases 
with  high-grade  anemia. 


Either  polynuclear  neutrophiles  or  lymphocytes 
may  be  relatively  increased,  more  commonly  the 
former. 

Small  numbers  of  myelocytes  in  very  anemic 
cases. 

Eosinophiles  not  increased. 
Basophiles  not  increased. 


The  absence  of  characteristic  blood  changes  in  Hodgkin's 
disease  at  once  distinguishes  the  condition  from  its  clinical  coun- 
terfeit, leukemia,  but,  aside  from  this  single  disease,  the  blood  ex- 


Leucocytes. 


Normal  or  moderately  increased. 


Plaques. 


Usually  increased. 


HODG KIN'S  DISEASE. 


331 


amination  is  valueless  in  the  differentiation  of  other  conditions 
having  somewhat  similar  involvement  of  the  glandular  structures. 
These  conditions,  tuberculous  and  syphilitic  adenitis,  local  lympho- 
matous  tumors,  and  malignant  neoplasms  of  the  lymphatics,  must 
therefore  be  distinguished  from  Hodgkin's  disease  by  other  clin- 
ical methods,  for  all  may  provoke  identical  blood  changes. 

In  reviewing  the  clinical  history  of  a  case  of  suspected  Hodg- 
kin's disease  the  following  symptoms  should  be  given  special 
consideration:  the  gradual  onset  of  a  widespread  hyperplasia  of 
the  lymphatic  structures,  occurring  most  commonly  in  males 
under  middle  age;  the  progressive  character  and  chronicity  in 
most  cases  of  the  disorder;  the  tendency  in  some  cases  toward 
the  occurrence  of  unexplained  febrile  periods,  sometimes  coincid- 
ing with  a  rapid  and  marked  increase  in  the  size  of  the  affected 
glands  which  disappears  as  the  fever  subsides;  the  cachexia, 
asthenia,  and  emaciation  of  the  patient,  frequently  associated  with 
gastro-intestinal  and  circulatory  disturbances  and  with  a  tendency 
to  hemorrhages,  such  as  epistaxis  and  purpura;  the  presence  of 
pressure  symptoms,  such  as  cough,  dysphagia,  dyspnea,  edema, 
and  pleural  and  peritoneal  effusions;  and  the  development  of 
bronzing  of  the  skin  in  an  occasional  case. 

In  typical  cases  the  glandular  enlargement  forms  a  series  of 
distinct,  painless,  hard  tumors,  each  freely  separable  frorn  its 
neighbor,  and  rarely  caseating  or  suppurating.  Due  weight 
should  also  be  given  to  the  fact  that  in  the  majority  of  cases  the 
lesion  originates  in  the  superficial  lymphatic  glands  of  the  cervical 
region,  beginning  either  in  the  occipital  or  in  the  inferior  carotid 
triangle.  The  spleen  is  moderately  enlarged  in  the  majority  of 
cases,  and  in  others  the  liver,  kidneys,  suprarenals,  tonsils,  thymus, 
thyroid,  and  sexual  organs  may  be  involved  in  the  lymphoid 
growths. 

As  in  leukemia,  remarkable  improvement  in  the  blood  and 
other  clinical  features  of  Hodgkin's  disease  is  reported  by  Senn,1 
by  Steinwald,2  by  Childs,3  and  by  Pusey4  as  the  result  of  ^-ray 
treatment. 

Tuberculous  adenitis  usually  first  involves  a  group  of  glands  in 
the  submaxillary  triangle,  and  tends  to  produce  inflammatory 
adhesions  between  the  tissues  and  the  glandular  structure,  with 
softening,  fusing,  caseation,  and  suppuration  of  the  glands.  It  is 
of  sluggish  development,  often  occurs  in  the  very  young,  and  is 

1  N.  Y.  Med.  Jour.,  1903,  vol.  lxxvii,  p.  665. 

2  Medicine,  1904,  vol.  x,  p.  438. 

3  N.  Y.  Med.  Jour.,  1904,  vol.  lxxx,  p.  13. 

4  Jour.  Amer.  Med.  Assoc.,  1902,  vol.  xxxviii,  p.  911. 


332 


DISEASES  OF  THE  BLOOD. 


almost  always  confined  to  a  single  group  of  glands.  Evidences 
of  tuberculous  lesions  in  the  lungs  or  in  other  parts  of  the  body, 
especially  of  dental  caries,  cutaneous  lesions  of  the  face,  and  ade- 
noid pharyngeal  growths,  and  the  discovery  of  tubercle  bacilli  in 
the  glandular  tissue  are  valuable  evidences  of  the  tuberculous 
nature  of  the  disease,  yet  they  do  not  positively  exclude  Hodg- 
kin's disease,  since  the  coexistence  of  the  two  conditions  in  the 
same  individual  is  possible  beyond  a  doubt.  Sternberg's  belief1 
that  Hodgkin's  disease  is  essentially  tuberculosis  is  still  supported 
by  Musser2  and  Sailer,3  although  the  recent  brilliant  work  of 
Dorothy  Reed,4  of  Longcope,5  and  of  Simmons 6  is  convincing  proof 
that  the  disease  is  a  distinct  clinical  entity,  in  no  way  related 
pathologically  to  the  tubercle  bacillus. 

In  syphilitic  adenitis  of  the  neck  the  post-cervical  groups  are 
first  affected,  the  glands  being  of  cartilaginous  hardness,  painless, 
freely  movable,  and  of  small  or  moderate  size.  The  glandu- 
lar enlargement  is  often  more  or  less  general,  but  the  affected 
groups  do  not  attain  a  large  size.  A  history  of  an  initial  lesion 
in  the  vicinity  of  the  primary  glandular  swellings,  or  of  the  ap- 
pearance of  secondary  symptoms,  the  disappearance  of  the  glan- 
dular tumors  after  the  administration  of  mercury,  and  the  pres- 
ence of  Justus'  test  will  suffice  to  prove  the  specific  character  of 
the  hyperplasia. 

A  local  lymphoma  is  limited  strictly  to  a  single  group  of  glands, 
forming  a  painless,  dense  mass,  free  from  inflammatory  adhesions, 
caseation,  and  suppuration.  It  commonly  involves  the  submaxil- 
lary glands,  may  attain  a  large  size,  and  is  unassociated  with  con- 
stitutional symptoms.  Such  a  local  lymphatic  tumor  cannot  be 
distinguished  from  the  early  stage  of  Hodgkin's  disease,  for  in 
some  cases  of  the  latter  the  general  lymphoid  hyperplasia  is  pre- 
ceded by  a  period  during  which  the  only  sign  of  the  condition  is 
a  localized  enlargement  of  a  single  group  of  glands.  If,  accord- 
ing to  Osier,7  a  local  tumor  of  this  kind  persists  for  over  a  year 
or  eighteen  months  without  involving  the  glands  of  the  opposite 
side  or  of  the  axilla,  it  is  almost  certainly  a  non-malignant 
lymphoma. 

Sarcoma  of  the  lymphatic  tissue  forms  an  immovable  tumor, 
early  complicated  by  inflammatory  processes  which  cause  inter- 
glandular  adhesions  and  adhesions  between  the  glands  and  the 

1  Zeitschr.  f.  Heilk.,  1898,  vol.  xix,  p.  21.       2  Amer.  Med.,  1902,  vol.  iii,  p.  13. 

3  Phila.  Med.  Jour.,  1902,  vol.  x,  pp.  615  and  669. 

4  Johns  Hopkins  Hosp.  Rep.,  1902,  vol.  x,  p.  133. 

5  Bull.  Ayer  Clin.  Lab.,  Penna.  Hosp.,  1903,  vol.  i,  p.  4. 
.    6  Jour.  Med.  Research,  1903,  vol.  ix,  p.  378. 

7  Cited  by  Bramwell,  "Anemia,"  Philadelphia,  1899,  p.  203. 


THE  EFFECT  ON  THE  BLOOD  OF  SPLENECTOMY.  333 

surrounding  tissues.  The  swelling  is  often  red  and  inflamed,  pits 
upon  pressure,  and  resembles  an  abscess,  while  the  skin  over  the 
site  of  the  lesion  is  frequently  marked  by  a  maze  of  tortuous, 
congested,  cutaneous  veins,  and  is  prone  to  ulcerate.  If  nerves 
are  entangled  in  the  growth,  the  tumor  is  exquisitely  painful. 
The  adjacent  tissues  become  densely  infiltrated  by  the  sarcomatous 
growth,  and  involvement  of  distant  organs  by  metastasis  is  likely 
to  occur.  If  such  be  the  case,  microscopical  search  for  sarcoma 
cells  in  the  fresh  specimen  may  give  a  definite  clue.  (See  "  Sar- 
coma," Section  VII.)  Sarcoma  of  the  lymphatic  glands  may 
occur  at  any  period  of  life. 

Carcinoma  of  the  lymphatic  glands  is  secondary  to  an  initial 
growth  in  some  other  part  of  the  body,  so  that  in  the  region  of 
the  neck  search  should  be  made  for  a  primary  cancerous  lesion 
in  the  mouth  and  upper  air-passages.  The  disease  is  most  com- 
monly found  during  the  decline  of  life. 

Finally,  as  Tyson  so  pertinently  remarks,1  it  should  not  be  for- 
gotten that  all  the  conditions  named  as  possible  to  be  mistaken 
for  Hodgkin's  disease  are  limited  to  a  single  group  of  glands, 
while  Hodgkin's  disease  always  extends,  and  the  fact  of  such 
limitation  is  of  itself  sufficient  to  exclude  the  disease.  This  pro- 
gressive involvement  of  the  lymphatic  glands,  group  after  group, 
must,  after  all,  be  the  mainstay  in  the  diagnosis  of  doubtful  cases. 


VIII.    THE  EFFECT  ON  THE  BLOOD  OF  SPLENEC- 
TOMY. 

Excision  of  the  spleen  in  man  is  followed  by  a 
Hemoglobin  diminution  in  the  hemoglobin  and  erythrocytes, 
and  the  degree  of  which  is  generally  believed  to  be 

Erythrocytes,  more  pronounced  than  can  be  accounted  for  by 
the  simple  factor  of  hemorrhage  incident  to  the 
operation.  Blood  regeneration  is  slow,  especially  the  restoration 
of  the  hemoglobin,  which  is  prone  to  increase  much  less  rapidly 
than  is  the  rule  in  an  ordinary  secondary  anemia.  In  uncompli- 
cated cases  from  one  to  three  months'  time  usually  elapses  be- 
fore the  normal  percentages  of  hemoglobin  and  erythrocytes  are 
attained;  in  unfavorable  cases  persistence  of  the  anemia  for  a 
much  longer  period  is  to  be  observed.  Splenectomies  attended 
by  great  loss  of  blood  may  excite,  in  addition  to  an  extreme  cel- 
lular decrease,  striking  qualitative  changes,  and  in  s.uch  instances 
the  blood  picture  is  characterized  by  the  presence  of  many  normo- 

1  "Practice  of  Medicine,"  Philadelphia,  1898,  p.  606. 


334 


DISK  ASKS   OK   THK  BLOOD. 


blasts,  achromacytes,  and  corpuscles  deformed  in  shape  and  size. 
Conspicuous  post-operative  anemia  is  especially  common  in  pa- 
tients to  whom  saline  intravenous  injections  have  been  admin- 
istered. 


TABLE  XVII.— THE  EFFECT  ON  THE  BLOOD  OF  SPLENECTOMY 


Number. 

Hemoglobin. 

Erythrocytes. 

Leucocytes. 

Small  Lym- 
phocytes. 

Large  Lym-  j 
phocytes. 

Polynuclear 
Neutrophiles. 

m 
W 

0 
ft 

0 

a 

O 

m 

Notes. 

I  1 

65 
65 

45 

45 
40 

40 
52.5 

5,200,000 
5,000,000 

3,256,000 

4,4.96,000 

3,984,000 

4,000,000 
4,672,000 

2,200 

24,000 
21,400 
23,800 
18,000 
18,000 
24,000 

16,400 
17,000 

20,000 

15,000 
21,600 

16,000 

22 
3-6 

7-9 

7.8 
9 

5-8 
15.8 

5-6 

5 

3\  2 
8.5 
9 

7-4 

7-4 
8.8 

10.2 

70 
93 

81 

76.8 

82.2 

82.8 
73-4 

79.8 

3 

0.2 

2.6 

6.2 
1.4 

4 

3-5 

Before  operation. 
Megaloblasts  and  nor- 
moblasts found. 

2  days  after  operation. 

3 

4  "  - 

5  "  " 
8  " 

11    "      "  " 
Myelocytes    and  mast 

cells  found.  No  eryth- 

roblasts. 

16  days  after  operation. 
21    "      "  " 
Myelocytes,  0.2  per  cent. 
27  days  after  operation. 
No  erythroblasts. 
37  days  after  operation. 

Myelocytes  found;  no 

erythroblasts. 
99  days  after  operation. 
Erythrocytes  normal. 

108 
100 
105 
63 

4,850,000 
4,700,000 
3,630,000 
2,750,000 

30,000 
39,000 
18,000 
20,000 

8 
5 

15 
5 

8 

4 
6 
10 

83 
9i 
78 
84 

1 
0 
1 
1 

Before  operation. 

7  days  after  operation. 
60    "  " 

3  years  " 

45 
87 
110 
100 

1,634,000 
2,460,000 
4,530,000 
3,977,000 

12,000 
20,000 
27,000 
8,000 

16 
18 
18 

21 

20 
32 
15 
11 

61 

49 
66 
62 

3 
1 
1 
6 

14  days  " 

27     "  " 

33    "  " 

2  years  and  six  months 
after  operation. 

63 
64 

77 
66 

85 
85 

4,570,000 
4,970,000 
5,180,000 
4,800,000 

4>353>000 
3,300,000 

8,000 
30,000 
65,000 

I7>5°° 
11,700 
11,600 

Before  operation. 

3  days  after  operation. 
6    "  " 

48    "  " 

4  m'ths  " 

5  years  " 

1  Warren,  Annals  of  Surgery,  1901,  vol.  xxxiii,  p.  513. 

2  Hartmann  and  Vaquez,  Compt.  rend  Soc.  biol.,  Paris,  1897,  vol.  iv,  p.  126. 

3  Ibid.      4  Czerny,  cited  by  Vulpius,  Beitrage  z.  klin.  Chir.,  1894,  vol.  xi,  p.  633 


THE  EFFECT  ON  THE  BLOOD  OF  SPLENECTOMY.  335 


Table  XVII. — The  Effect  on  the  Blood  of  Splenectomy. — {Continued.) 


Number. 

1 

Hemoglobin. 

Erythrocytes. 

Leucocytes. 

Small  Lym- 
phocytes. 

T  T 

Large  Lym- 
phocytes. 

w  t/3 
<  S 

w  p 

IB 

Eosinophiles. 

Notes. 

51 

60 
72 

77 

4,300,000 
4,408,000 
4,420,000 

22,000 
13,000 
11,200 

14 
T3 
12 

8 

19 
18. 1 

77 

66.5 

65.2 

2 

i-5 

2 

6  days  after  operation. 
19    "  " 
26  " 

Normoblasts  found. 

62 

83 

85 
82 
86 
90 
92 

3,280,000 
3,980,000 
4,480,000 
4,280,000 
4,300,000 
4,220,000 
4,630,000 

22,000 
26,000 
24,000 
18,000 
12,000 
10,000 
12,000 

33 
27 

4' 

5  * 

53 
63 

10 

3 

4  days  after  operation. 

8  " 

14    -  - 
18  " 
25  " 
30  " 
52 

73 

40 
5° 

75 

4,100,000 
4,370,000 
4,300,000 

4,500,000 
4,480,000 

60,000 
46,000 
38,000 
26,000 
17,000 
25,000 
10,400 

6 

11.4 

7-i 
14-3 

12 
8.6 

30.1 
17. 1 

81.6 

78.9 

60.1 
61.9 

o-3 
I.I 

2-3 

6.7 

7  days  after  operation. 

15    "  " 
19    «  << 
38    <<  " 
46 

2  m'ths  "  " 
5     "  " 

8* 

24 
12 
15 
19 
16 

7 
8 

5 

.  7 
8 

67 

77 

80 

7i 
72 

2 

3 
I 

3 
4 

Before  operation. 

7  days  after  operation. 
30  " 

45    "  " 
90    "  " 

Q7 

IOI 

in 
9i 
73 
85 
93 

102 

4,700,000 
5,600,000 
4,500,000 
3,900,000 
3,500,000 
4,000,000 
5,300,000 

5.700 
12,300 
15,000 
11,300 
10,000 
8,000 
7>5oo 

59-i 
42.9 
18.0 

30-5 
26.7 

32-9 
35-9 

2.2 

i-7 
1.9 
2.2 
1.8 
2.7 
i-7 

59-i 

Cot 
78.6 
65.6 
67.9 
58.8 
58.5 

4.2 
3-2 
1.4 

i-5 
3-5 
5-5 
3-7 

60  days  after  operation. 
91 

128  " 

138    "  » 

161  " 

212    "      "  " 
13  m'ths  "  " 
Mast  cells  ranged  from 
0.15  to  0.3  per  cent. 

Post-operative  leucocytosis  of  the  polynuclear 
Leucocytes,  neutrophile  type  develops  promptly,  and  persists 
in  most  instances  for  from  four  to  six  weeks,  ac- 
cording to  Hartmann  and  Vaquez,6  but  occasionally  for  a  longer 
period.    Counts  of  between  15,000  and  30,000  represent  the  grade 

1  Tieken,  Jour.  Amer.  Med.  Assoc.,  1903,  vol.  xl,  p.  887. 

2  Ballance,  Practitioner,  1898,  vol.  lx,  p.  347. 

3  Heaton,  Brit.  Med.  Jour.,  1899,  vol.  ii,  p.  476. 

4  Hartmann  and  Vaquez,  cited  by  Bordet,  "Des  modifications  du  sang  apres 
la  splenectomie,"  These,  Paris,  1897. 

5  Staehelin,  Deutsch.  Arch.  f.  klin.  Med.,  1903,  vol.  lxxvi,  p.  364. 

6  Compt.  rend.  Soc.  biol.,  Paris,  1897,  vol.  iv,  p.  126. 


336  DISEASES  OF  THE  BLOOD. 

of  leucocytosis  ordinarily  found,  although  occasionally  the  increase 
is  far  greater— 70,000  in  a  case  cited  by  Czerny,1  and  75,000  in 
one  reported  by  Hartley.2    After  a  number  of  months,  even  as 
late  as  the  second  or  third  year  after  the  operation,  there  is  a 
moderate  increase  in  the  number  of  eosinophiles.  Small-celled 
lymphocytosis  is  a  frequent  but  inconstant  change,  the  develop- 
ment and  duration  of  which  vary  greatly.    It  is  supposed  to  reflect 
hyperactivity  of  the  lymphatic  glands.    Eosinophilia  commonly 
develops  within  a  few  months,  as  in  a  case  studied  by  Rauten- 
berg,3  in  which  the  eosinophiles  increased  to  six  times  the  normal 
percentage  by  the  fourth  week*  after  the  operation.     In  splen- 
ectomized  guinea-pigs  Kurloff4  found  during  the  first  year  after 
the  operation  a  marked  lymphocytosis,  as  high  as  60  per  cent, 
in  some  animals,,  together  with  a  corresponding  decrease  m  the 
number  of  granular  cells,  but  with  no  alteration  in  the  num- 
ber of  large  mononuclear  leucocytes.    Eosinophilia  became  ap- 
parent during  the  second  year,  and  coincidentally  with  this  change 
a  decrease  in  the  lymphocytes  to  their  normal  percentage  took 
place.    In  splenectomized  dogs  Nicholas  and  Dumoulin5  noted 
post-operative  leucopenia,  succeeded  by  eosinophilia  and  by 
lymphocytosis,  which,  after  several  months,  was  followed  by  a 
gradual,  progressive  lymphocyte  decrease.    The  polynuclear  neu- 
trophiles  showed'  relatively  high  percentages,  but  were  not  de- 
cidedly increased. 

The  above  remarks  concerning  the  differential  changes  alter- 
ing the  leucocytes  after  splenectomy  must  be  regarded  as  tenta- 
tive, in  view  of  the  fact  that  sufficient  data  bearing  upon  this 
question  have  not  yet  accumulated  to  justify  more  definite  con- 
clusions. Enlargement  of  the  lymph  glands,  bone  pains,  and  a 
marked  susceptibility  to  various  infections  are  frequent  post- 
operative phenomena  in  splenectomized  individuals. 

The  table  on  page  334  shows  the  condition  of  the  blood  in  the 
few  recorded  cases  in  which  thorough  blood  examinations  have 
been  carried  out.  Reports  of  other  cases  may  be  found  m  Staehe- 
lin's  monograph,  referred  to  above.  ; 

It  is  to  be  remembered  that,  aside  from  the  character  ot  the 
splenic  lesion,  these  important  factors  also  determine  the  degree 
of  the  post-operative  anemia  and  leucocytosis  in  this  procedure: 
the  grade  of  the  preexisting  anemia,  the  amount  of  hemorrhage 
during  the  following  operation,  and  the  patient's  recuperative 
powers.    All  things  being  equal,  the  anemia  is  least  marked  and 

1  L     cit  2  Med.  News,  1898,  vol.  lxxii,  p.  417. 

"  Deutsch.  Zeitschr.  f .  Chir.,  1902,  vol.  lxiv,  p.  352.  4  Cited  by  Ehrlich,  loc.  cit. 
5  Journ.  de  phys.  et  de  path,  gen.,  1903,  vol.  v,  p.  1073. 


Hodgkin's  Disease. 

Normal  or  moderate  decrease, 
averaging  to  about  60  per  cent. 

Relatively  high  or  low  to  ery- 
throcyte loss. 

Normal  or  moderate  decrease, 
counts  averaging  about  3,500,000. 

Pallor  usually  not  notably  marked. 

Poikilocvtosis  usually  absent  or 
slight. 

Erythroblasts  extremely  rare,  nor- 
moblasts predominating. 

Polychromatophilia  and  basic 
stroma  degeneration  usually 
absent. 

Changes  in  diameter  variable. 

Subnormal,  averaging  about  0.80. 

Normal  or  slightly  increased, 
counts  averaging  about  10,000. 

Polynuclear  neutrophiles  normal 
or  increased,  with  consequent 
lymphocyte  decrease  ;  rarely,  an 
increase  in  lymphocytes. 

Myelocytes  rare. 

Eosinophiles  normal  or  decreased. 
Basophiles  not  increased. 

Increased.                               Usually  increased. 

Myelogenous 
Leukemia. 

Decided  decrease,  averaging 

to  about  50  per  cent. 
Relatively  low  to  erythrocyte 

loss. 

Decided  decrease,  counts 
averaging  about  3,000,000. 

Pallor  usually  marked. 

Poikilocytosis  variable,  often 
excessive. 

Erythroblasts  numerous,  nor- 
moblasts predominating. 

Polychromatophilia  and  basic 
stroma  degeneration  com- 
mon. 

Changes  in  diameter  variable. 

Subnormal,  averaging  about 

0.90. 

Striking  increase,  counts 
averaging  about  350,000. 

Excessive  myelocyte  increase, 
with  polynuclear  and  lym- 
phocyte decrease. 

Eosinophiles      always  in- 
creased. 

Basophiles     strikingly  in- 
creased. 

Lymphatic  Leukemia. 

Decided  decrease,  averaging 

to  about  60  per  cent. 
Relatively  very  low  to  ery- 
throcyte loss. 

Decided  decrease.  counts 
averaging  about  3,000,000. 

Pallor  usually  marked. 

Poikilocytosis  variable,  often 
excessive. 

Erythroblasts  rare,  normo- 
blasts predominating. 

Polychromatophilia  and  basic 
stroma  degeneration  com- 
mon. 

Changes  in  diameter  variable. 

Low,  averaging  about  0.60. 

Marked  increase,  counts 
averaging  about  250,000. 

Excessive  lymphocyte  in- 
crease with  polynuclear 
neutrophile  decrease. 

Small  numbers  of  myelocytes 
common. 

Eosinophiles  .  usually  not  in- 
creased. 

Basophiles    not   greatly  in- 
creased. 

Increased. 

Absolute  Lympho- 
cytosis. 

Unchanged. 

Unchanged. 

Unchanged. 

Increased,  rarely  to 
more  than  25,000. 

Moderate  lymphocyte 
increase,  with  poly- 
nuclear neutrophile 
decrease. 

Myelocytes  uncom- 
mon. 

Eosinophiles  usually 
decreased. 

Basophiles    not  in- 
creased. 

Not  increased. 

Leucocytosis. 

Unchanged. 

Unchanged. 

Unchanged. 

Increased,  rarely  to 
more  than  50,000. 

Excessive  polynuclear 
neutrophile  increase 
with  lymphocyte  de- 
crease. 

Small  numbers  of  my- 
elocytes occasion- 
ally present. 

Eosinophiles  almost 
invariably  de- 

Basophiles     not  in- 
creased. 

Variable. 

Hemoglobin. 

Erythrocytes. 

Color  Index. 

Leucocytes. 

Plaques. 

337 


338 


DISEASES  OF  THE  BLOOD. 


the  blood  regeneration  most  prompt  in  simple  wandering  spleen 
and  in  ague  cake,  while  blood  deterioration  is  more  marked  and 
regeneration  slower  in  rupture  of  this  organ.  Splenectomy  for 
myelogenous  leukemia  is  almost  invariably  followed  by  a  pro- 
gressive anemia  and  leucocytosis,  and  in  nearly  all  cases  by  death. 
But  five  recoveries  after  removal  of  the  spleen  in  this  disease 
have  been  reported,1  the  operation  having  been  performed  in 
forty-two  cases. 

^agen,  Arch.  f.  klin.  Chir.,  1900,  vol.  v,  p.  188;  also  Richardson,  cited  by 
Warren,  loc.  cit. 


SECTION  VI. 


THE  ANEMIAS  OF  INFANCY  AND 
CHILDHOOD. 


SECTION  VI. 
THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 


I.  CHARACTERISTICS  OF  THE  BLOOD  IN  CHILDREN. 

As  a  preliminary  essential  to  the  intelligent 
Fetal  Blood,  study  of  the  various  pathological  conditions  of 
the  blood  in  children  it  is  necessary  briefly  to 
refer  to  certain  points  of  difference  in  the  composition  of  this  tis- 
sue in  the  child  and  in  the  adult.  In  general  terms  it  may  be 
stated  that  the  younger  the  child,  the  more  unformed  are  the 
different  elements  of  the  blood  and  the  nearer  its  composition 
resembles  the  blood  of  the  fetus. 

In  fetal  blood  the  specific  gravity,  both  of  the  whole  blood  and 
of  the  serum,  is  lower  than  in  the  adult,  and  coagulation  is  very 
slow  and  imperfect.  The  erythrocytes  vary  greatly  in  size  and  in 
shape,  and  are  deficient  in  hemoglobin,  which  is  loosely  attached 
to  these  cells  and  hence  becomes  readily  dissolved  out.  Zang- 
meister  and  Meissl1  conclude  that,  in  comparison  with  maternal 
blood,  fetal  blood  is  poorer  in  albumin  and  nitrogen  and  is  less 
active  in  agglutinative,  bactericidal,  and  immunizing  powers. 

Until  about  the  seventh  month  of  intra-uterine  life  normo- 
blasts constitute  the  predominating  variety  of  erythrocytes,  after 
which  period  they  rapidly  diminish  in  number,  until  at  full  term 
few,  if  any,  nucleated  red  corpuscles  are  found  in  the  blood.  Of 
the  different  varieties  of  leucocytes,  the  mononuclear  forms  are 
present  in  a  proportion  relatively  excessive  to  the  other  varieties; 
before  the  seventh  month  this  lymphocytosis  is  due  to  a  high 
relative  percentage  of  large  lymphocytes,  but  after  this  period 
the  proportion  of  small  lymphocytes  increases,  until  finally 
they  predominate.  The  percentage  of  eosinophiles  reaches  its 
maximum  at  the  seventh  month,  gradually  becoming  less  and  less 
as  the  end  of  the  intra-uterine  life  approaches. 

We  find,  therefore,  that  in  the  fetus  the  blood  is  characterized 
chiefly  by  the  presence  of  large  numbers  of  normoblasts,  by  a 
high  relative  proportion  of  mononuclear  leucocytes,  by  a  deficiency 

1  Munch,  med.  Wochenschr.,  1903,  vol.  1,  p.  673. 
34i 


342  THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 

of  hemoglobin,  and  by  a  feeble  activity  of  the  serum.  The  closer 
an  infant's  blood  resembles  this  picture,  the  "younger"  in  point 
of  development  is  such  blood  considered,  and  the  more  strongly  is 
it  said  to  revert  to  a  "young"  or  "embryonal"  type.  The  deficient 
defensive  potency  of  the  blood  of  the  young  baby  may  account  for 
the  proneness  of  infants  toward  infections  in  general. 

At  birth  the  blood  of  the  full-term  infant  is  of 
The  Blood    higher  specific  gravity  and  richer  in  hemoglobin 

at  Birth.     and  in  corpuscular  elements  than  that  of  the  older 
child  or  of  the  adult. 

The  specific  gravity  of  the  blood  of  the  average  healthy  infant 
at  the  time  of  birth  and  during  the  first  few  weeks  of  life  is,  ap- 
proximately, 1.066.  For  normal  children  the  average,  which  is 
reached  by  the  beginning  of  the  second  year,  varies  from  1 .050  to 
1.058,  being  slightly  higher  in  boys  than  in  girls. 

The  maximum  amount  of  hemoglobin  is  found  at  birth,  the 
percentage  at  this  time  ranging  from  100  to  104,  according  to 
the  investigations  of  Hammerschlag.1  After  birth  the  amount  of 
hemoglobin  immediately  begins  to  diminish,  the  minimum,  which 
may  be  as  low  as  55  or  60  per  cent.,  being  attained  by  the  end 
of  the  third  week  of  life.  It  remains  at  or  about  this  minimum 
for  a  variable  period  of  time — sometimes  for  as  long  as  six  months 
— and  then  gradually  begins  to  increase. 

At  birth  the  number  of  erythrocytes  in  the  peripheral  blood  is 
decidedly  higher  than  normal,  counts  of  between  5,500,000  and 
6,000,000  cells  per  c.mm.  being  found  at  this  time,  the  highest 
figures  being  observed  in  those  cases  in  which  ligation  of  the 
umbilical  cord  has  been  delayed.  During  the  first  twenty- 
four  hours  of  extra-uterine  life  this  polycythemia  becomes  still 
more  marked,  so  that  the  number  of  corpuscles  per  c.mm.  may 
reach  a  maximum  of  from  7,000,000  to  8,000,000,  and  sometimes 
higher,  by  the  end  of  the  first  day.  Beginning  with  the  second  day, 
a  gradual  diminution  in  the  number  of  these  cells  is  noticed,  and 
the  normal  5,000,000  per  c.mm.  is  reached  by  the  end  of  the  first 
week  or  ten  days.  Hayem2  emphasizes  the  fact  that  the  fluctua- 
tions in  the  number  of  erythrocytes  during  the  early  days  of  life 
stand  in  inverse  ratio  to  the  variations  in  the  weight  of  the  child, 
the  maximum  number  being  found  at  the  time  of  the  infant's 
minimum  weight,  while  as  the  child  begins  to  gain  in  weight  the 
count  decreases.  Schiff3  is  inclined  to  attribute  these  fluctuations 
to  the  amount  of  liquids  in  the  body,  the  result  of  feeding,  showing 

1  Centralbl.  f.  klin.  Med.,  1891,  vol.  xii,  p.  825. 

2  "Du  Sang,"  etc.,  Paris,  1889. 

3  Zeitschr.  f.  Heilk.,  1890,  vol.  xi,  p.  17. 


CHARACTERISTICS  OF  THE  BLOOD  IN  CHILDREN.  343 


that  in  fasting  children  the  counts  arc  always  higher  than  in  those 
fed  at  frequent  intervals. 

Whatever  may  be  the  exact  manner  of  their  production,  it  is 
evident  that  these  fluctuations  arc  to  be  regarded  as  purely  physio- 
logical in  character,  depending  upon  concentration  and  dilution 
of  the  blood,  rather  than  as  an  expression  of  involvement  of  the 
blood-making  organs. 

The  erythrocytes  vary  greatly  in  size  during  the  first  few  days 
of  post-natal  life,  the  diameter  of  some  cells  being  as  small  as 
3.25  ft  and  of  others  as  large  as  10.25  fi.  Many  observers  have 
noticed  that  the  small-sized  cells,  as  a  rule,  predominate.  Such  a 
microcytosis  in  the  adult  would  mean  well-defined  anemia. 

Nucleated  erythrocytes  of  the  normoblastic  type  may  or  may 
not  be  present  in  the  blood  of  new-born  infants;  they  are  com- 
monly found  in  large  numbers  in  the  prematurely-born  child,  and 
also  occur  less  numerously  in  many  fully  developed  babies,  not- 
withstanding views  to  the  contrary  expressed  by  some  observers, 
notably  by  Hayem1  and  by  Fischl.2  In  most  cases  normoblasts 
disappear  from  the  blood  after  the  first  few  days  of  life,  and  their 
presence  after  the  sixth  month  should  always  be  regarded  as 
pathological. 

The  number  of  leucocytes  at  birth  averages  about  20,000  per 
c.mm.,  the  normal  average  for  young  infants,  15,000  per  c.mm.,  be- 
ing reached  by  the  end  of  the  first  week,  after  numerical  fluctua- 
tions similar  to  those  affecting  the  erythrocytes.  From  the  second 
or  third  week  until  the  sixth  month  a  count  from  10,000  to  14,000 
may  be  regarded  as  normal,  while  for  the  child  of  one  year  of  age 
the  average  is  about  10,000.  By  the  sixth  year  the  number  of 
leucocytes  falls  to  the  number  normal  for  the  adult,  7500  per 
c.mm.  The  following  excellent  table  from  Rotch3  shows  these 
average  counts  of  erythrocytes  and  leucocytes  in  children  from 
birth  until  the  sixth  year  of  age: 


Age.  Erythrocytes.  Leucocytes. 

At  birth   5,900,000  21,000  (26,000  to  36,000 

after  first  feeding) . 

End  of  1st  day   7,000,000  to  8,000,000  .  24,000 

"     2d    "    Generally  increased.  30,000 

"     4th   "    6,000,000  20,000 

"     7th  "    5,000,000  15,000 

10th  day     10,000  to  14,000 

12th  to  18th  day     12,000 

1st  year     10,000 

6th  year  and  upward     7, 5  00 


1  hoc.  cit. 

2  Zeitschr.  f.  Heilk.,  1892,  vol.  xiii,  p.  277. 

3  "Pediatrics,"  Philadelphia,  1896,  p.  342. 


344 


THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 


The  influence  of  the  initial  feeding  in  infants  produces  a 
marked  leucocytosis,  the  increase  amounting  to  from  5000  to 
15,000  per  c.mm.,  as  shown  by  the  above  table.  It  is  probable 
that  the  habitual  leucocytosis  of  early  childhood  is  largely  refer- 
able to  a  more  or  less  continuous  digestion  leucocytosis.  (For  a 
further  discussion  of  this  question  see  "  Digestion  Leucocytosis," 
P-  2.31-) 

The  blood  of  infants  and  of  young  children  differs  greatly  from 
that  of  the  adult  in  the  relative  proportions  0)  the  different  forms 
of  leucocytes,  these  qualitative  differences  becoming  less  and  less 
apparent  as  the  child  grows  older,  and  not  usually  persisting 
beyond  the  tenth  year.  In  general  terms  it  may  be  said  that 
these  dissimilarities  are  striking  in  relation  to  the  youth  of  the 
child.  Compared  to  the  adult,  a  differential  count  of  the  leuco- 
cytes in  the  child  shows  that  the  relative  percentage  of  lympho- 
cytes is  more  than  twice  as  great,  and  of  polynuclear  neutrophiles 
one-half  as  great,  while  the  proportion  of  eosinophiles  is  frequently 
much  higher.  In  the  following  table,  based  upon  data  given  by 
Gundobin,1  these  points  of  difference  are  contrasted: 

Forms  of  Leucocytes.  Infants.  Adults. 

Small  lymphocytes  .  .50   to  70  per  cent.  20    to  30  per  cent. 

Large  lymphocytes 
and  transitional 

forms    6    "  14  "     "  4     "   8  "  " 

Polynuclear  neutro- 
philes  28    "  40  "      "  60     "  75  "  " 

Eosinophiles   0.5  "  10  "      "  0.5  "    5  "  " 

It  is  important  to  take  into  account  these  differences  in  mak- 
ing blood  examinations  in  children,  in  whom  one  must  expect  to 
find  percentages  of  lymphocytes  which  in  the  adult  would  be 
regarded  as  abnormally  high. 

Many  of  the  lymphocytes  differ  from  corresponding  cells  in  the 
adult,  chiefly  in  being  of  larger  size,  in  exhibiting  a  greater  variety 
of  nuclear  figures,  and  in  having  a  more  basic  tendency.  Karnizki2 
also  professes  to  find  an  occasional  myelocyte  in  the  blood  of  the 
healthy  child,  and  to  trace  a  decided  morphological  resemblance 
between  the  lymphocytes,  the  transitional  forms,  and  the  neur 
trophiles.  While  it  is  true  that  myelocytes  appear  in  the  infant's 
blood  upon  slight  provocation,  one  can  scarcely  regard  them  as 
normal  elements;  nor  can  a  relationship  between  the  lymphatic 
and  the  myelogenous  leucocytes  be  established  more  clearly  in 
the  child  than  in  the  adult. 

Leucocytosis  in  children  is  of  extremely  common  occurrence, 

1  Jahrb.  f.  Kinderheilk.,  1893,  vol.  xxxv,  p.  187. 

2  Arch.  f.  Kinderheilk.,  1903,  vol.  xxxvi,  p.  42. 


ANEMIA  IN  CHILDREN. 


345 


often  arising  from  causes  of  the  most  trivial  character,  and  de- 
veloping to  a  greater  degree  and  with  much  more  rapidity  than 
in  the  adult.  It  is  therefore  to  be  regarded  with  less  significance 
than  when  it  occurs  in  the  mature.  Usually  the  polynuclear  cells 
are  chiefly  involved  in  the  increase,  but  the  inclination  of  the 
blood  of  children  to  revert  to  the  embryonic  type  appears  to 
cause,  in  many  cases,  a  disproportionate  increase  of  lymphocytes 
in  relation  to  the  other  forms,  this  peculiarity  being  especially 
true  of  the  various  pathological  leucocytoses.  Physiological  leu- 
cocytosis  in  children  usually  affects  chiefly  the  polynuclear  neu- 
trophile  cells. 

II.    ANEMIA  IN  CHILDREN. 

Children,  as  a  class,  are  peculiarly  susceptible 
Frequency,  to  anemia,  for  they  appear  to  lack  resisting  pow- 
ers against  the  influence  of  causes  tending  to  pro- 
duce pathological  alterations  in  the  blood.  Thus,  it  is  found  that 
the  same  factors  which  in  the  adult  have  little  or  no  effect  upon 
the  blood,  are  capable  of  producing  profound  alterations  in  its 
composition  in  the  child.  Severe  anemias  may  arise  in  children 
from  apparently  the  most  trivial  causes;  slight  hemorrhage  from 
the  navel,  for  instance,  may  light  up  an  anemia  of  an  intensity  out 
of  all  proportion  to  the  actual  amount  of  the  blood  loss,  while 
minor  lesions  of  the  gastro -intestinal  tract  are  commonly  asso- 
ciated with  blood  deterioration  of  a  severe  type. 

It  is  a  notable  fact  that  in  anemic  children  a 
General     predominant  tendency  exists  toward  a  reversion 
Character-   of  the  blood  to  a  less  mature  histological  type, 
istics.       such  as  that  found  in  the  blood  of  the  fetus. 

Thus  in  children  anemia  of  a  type  which  in  the 
adult  is  unattended  by  qualitative  changes  in  the  corpuscles  is 
commonly  associated  with  the  presence  of  large  numbers  of 
nucleated  erythrocytes,  these  cells  being  far  more  numerous  than 
the  severity  of  the  anemia  would  seem  to  warrant.  Megaloblasts 
are  not  of  the  same  significance  in  infancy  as  in  adult  life.  They 
may  occur  in  anemias  of  but  moderate  intensity — in  fact,  they  may 
predominate,  as  Morse  has  shown,1  without  necessarily  constituting 
a  sign  of  fatal  blood  disease.  In  Riviere's  experience2  megalo- 
blasts, in  ordinary  well-marked  infantile  anemias,  may  constitute 
between  20  and  50  per  cent,  of  the  erythroblasts,  the  ratio  of 
megaloblastic  forms  apparently  standing  in  no  definite  parallelism 

1  Boston  Med.  and  Surg.  Jour.,  1903,  vol.  cxlviii,  p.  573. 

2  Lancet,  1903,  vol.  ii,  p.  1419. 


346  THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 

to  the  severity  of  the  anemia  of  which  they  are  symptomatic. 
Poikilocytosis  and  dejormities  in  the  size  of  the  corpuscles  also 
occur  with  far  greater  frequency  than  in  the  adult.  Regeneration 
of  the  blood  takes  place  slowly.  The  oligochromemia  is  relatively 
greater  than  the  oligocythemia  in  most  anemias  of  children,  this 
being  due  probably  to  the  fact  that  the  hemoglobin  is  peculiarly 
prone  to  separate  from  the  corpuscular  stroma.  Owing  to  this  fact 
low  color  indices,  as  in  chlorosis,  are  common,  irrespective  of  the 
degree  of  corpuscular  diminution. 

Myelocytes  are  commonly  found  in  the  blood  in  all  the  anemias 
of  children;  they  are  present  in  larger  relative  percentages  and  in 
less  severe  pathological  conditions  than  in  the  adult.  The  writer 
has  noted  the  frequency,  almost  the  constancy,  with  which  typical 
mast  cells  and  the  fine  basophiles  occur  in  the  specific  infections  in 
children,  notably  in  enteric  fever  and  in  tuberculosis. 

Leucocytosis,  often  lymphocytosis,  and  enlargement  of  the 
spleen  are  frequently  associated  with  all  forms  of  anemia  in  the 
young ;  and  although  these  conditions  are  likely  to  coexist,  this  is  by 
no  means  the  invariable  rule.  Splenic  enlargement  is  especially 
common  in  the  anemias  due  to  syphilis,  rachitis,  tuberculosis, 
gastro-intestinal  disease,  malaria,  and  septic  infection. 

To  epitomize,  in  the  anemias  of  infancy  and  childhood  the 
following  prominent  features  of  the  blood  are  found:  (a)  The 
frequency  of  a  low  color  index;  (b)  the  common  occurrence  of 
erythroblasts  and  of  deformities  affecting  the  shape  and  size  of 
the  erythrocytes ;  (c)  a  tendency  toward  leucocytosis  and  splenic 
enlargement,  and  (d)  the  frequency  of  myelocytes  and  mast  cells. 

It  is  owing  to  these  peculiarities  that  the  clas- 
Classifica-    sincation  of  the  anemias  of  children  is  such  a  dif- 
tion.        ficult  matter.    The  older  classifications,  based 
upon  the  nature  of  the  causal  factors  of  the  an- 
emia and  upon  the  presence  or  absence  of  enlargement  of  the 
spleen,  have  failed  in  many  respects  to  prove  adequate,  so  that  it 
becomes  necessary  to  adopt  a  simpler  and  more  comprehensive 
division  from  which  no  exceptions  need  be  made  in  the  individual 
case.    Such  a  classification  has  been  suggested  by  Morse.1  This 
author  assuming,  and  rightly  so,  that  chlorosis  is  a  condition 
wholly  foreign  to  infantile  life,  and  that  the  disease  described 
by  von  Jaksch  as  "anemia  infantum  pseudoleukemica "  does  not 
represent  a  distinct  clinical  condition,  proposes  this  excellent 
classification,  slightly  modified  from  that  of  Monti: 
Primary  Anemia.  Pernicious  anemia. 

Leukemia.  . 

1  Arch.  Pediat.,  1898,  vol.  xv,  p.  815. 


ANEMIA  IN  CHILD R ION. 


347 


Secondary  Anemia.  Mild  anemia. 

Mild  anemia  with  leucocylosis. 
Severe  anemia. 

Severe  anemia  with  leucocytosis. 
Pernicious  anemia  is  rare  in  the  young,  and 

Primary      likely  to  be  mistaken  for  other  forms  of  severe  an- 

Anemia.  emia  secondary  to  various  conditions.  It  is  prob- 
able that  many  of  the  reported  cases  of  Biermer's 
anemia  in  infants  were  in  reality  examples  of  severe  secondary 
anemia.  Hutchinson/  in  his  Goulstonian  lectures,  gives  the 
data  of  1 1  authentic  cases,  the  total  number  recorded  up  to  the 
present  time.  The  apparent  tendency  of  pernicious  anemia  in 
children  to  become  transformed  into  leukemia  is  doubtless  more 
fanciful  than  real,  a  remark  which  is  equally  true  of  those  few 
reported  instances  of  the  conversion  of  leukemia  into  pernicious 
anemia.  In  the  first  case  the  erroneous  impression  may  arise  from 
such  evidence  as  marked  enlargement  of  the  spleen  associated  with 
a  high  leucocytosis;  in  the  second,  a  temporary  disappearance  of 
the  myelogenous  blood-picture  plus  an  aggravation  of  the  exist- 
ing anemia  may  be  sufficient  to  convey  the  false  impression.  It 
must  be  admitted  that  these  atypical  blood  changes,  so  common 
in  young  children,  are  highly  confusing  and  difficult  to  interpret 
without  the  closest  observation  and  the  correlation  of  other  clin- 
ical signs.    (See  "  Leukanemia,"  p.  290.) 

Infantile  pernicious  anemia  is  characterized  by  the  same  blood 
changes  that  are  found  in  the  adult,  in  so  far  as  striking  oligocy- 
themia and  deformities  of  the  erythrocytes  are  concerned,  but 
the  blood  often  fails  to  show  a  high  color  index.  A  prevalence 
of  megaloblasts  and  of  megalocytes  is  not  pathognomonic,  as 
it  is  in  the  adult. 

Splenic  anemia,  which  is  none  too  certain  an  entity  in  the  adult, 
can  rarely  be  identified  in  the  child.  The  splenic  enlargement 
in  most  reputed  instances  of  this  condition  in  early  life  must  be 
regarded  as  symptomatic  of  nutritive  disturbance,  rather  than  as 
a  distinctive  factor  of  anemia.  Hutchinson2  uses  the  terms  in- 
fantile splenic  anemia  and  infantile  pseudoleukemia  anemia 
synonymously,  and  believes  that  the  former  is  entirely  distinct 
from  splenic  anemia  of  the  adult.  It  must  be  admitted,  however, 
that  rarely  the  adult  type  of  the  disease  is  met  with  in  children,  as 
shown  by  the  cases  reported  by  Williamson,3  Hunt,4  Rolleston,5 

1  Lancet,  1904,  vol.  i,  pp.  1253  and  1325,  and  1402. 

2  Loc.  cit.  3  Med.  Chronicle,  1893,  vol.  xviii,  p.  103. 

4  Trans.  Path.  Soc.  London,  1899,  vol.  1,  p.  209. 

5  Clin.  Jour.,  1902,  vol.  xix,  p.  401. 


34§  THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 


Hamill,1  and  others.  Such  cases  show  the  same  type  of  anemia, 
leucopenia,  and  lymphocytosis  found  in  the  blood  of  the  adult 
suffering  from  this  disease. 

Leukemia  in  children  is  uncommon,  but  instances  have  been 
reported  during  all  stages  of  infancy  and  childhood,  even  in  the 
new-born.  Acute  forms  of  the  disease  are  most  frequently  met 
with,  the  great  majority  of  cases,  according  to  Holt,2  proving 
fatal  within  a  year  from  the  appearance  of  the  first  symptoms, 
while  in  many  the  disease  runs  its  course  in  a  few  weeks.  Lym- 
phatic leukemia  is  about  five  times  as  common  in  children  as 
myelogenous.  Male  children  are  more  commonly  leukemic  than 
female.  Conditions  such  as  rachitis,  syphilis,  and  malarial  fever 
have  been  regarded  by  some  authors  as  possessing  a  certain 
amount  of  importance  as  etiological  factors,  but  in  the  vast  ma- 
jority of  cases  the,  cause  of  the  disease  is  entirely  obscure. 

Of  the  several  collected  reports  of  leukemia  in  children,  the 
two  articles  of  Morse,  giving  a  total  of  27  cases,  are  by  far  the 
most  valuable.  In  his  first  communication3  20  cases  were  re- 
corded, including  one  of  his  own,  tabulated  below,  but  of  this 
series  the  diagnosis,  in  the  great  majority  of  instances  being  based 
either  upon  clinical  symptoms  or  upon  inadequate  examination 
of  the  blood,  the  reporter  is  led  to  remark  that  "it  is  highly  probable 
that  not  more  than  half,  perhaps  not  more  than  a  third,  of  these 
were  really  cases  of  leukemia."  In  Morse's  second  article,4 
which  deals  with  the  acute  form  of  the  disease,  seven  cases,  again 
including  one  of  his  own,  also  recorded  below,  are  reported. 

Although  the  literature  of  pediatrics  is  fairly  rich  in  alleged 
examples  of  leukemia  in  children,  the  cases,  with  but  a  few  ex- 
ceptions, are  reported  in  so  unsatisfactory  a  manner  that  they 
cannot  be  regarded  without  reserve  as  typical.  Those  reported 
prior  to  the  publication  of  Morse's  first  article— in  1894— must  all 
be  open  to  criticism,  owing  to  the  general  disregard  for  differen- 
tial counts  shown  by  the  various  authors,  and,  strangely  enough, 
this  criticism  must  hold  true  for  many  cases  recorded  during  the 
past  ten  years.  The  author  has  been  able  to  collect  21  cases 
(Table  XVIII),  in  all  of  which  the  differential  count  of  leuco- 
cytes leaves  no  doubt  as  to  the  precise  character  of  the  disease. 

In  addition  to  the  above  cases  several  others  have  been  reported 
in  which  the  differential  count  of  leucocytes  has  been  either  faultily 
made  or  entirely  neglected.    Thus,  Pollman5  believes  that  he  has 

1  Arch.  Pediat.,  1902,  vol.  xix,  p.  641. 

2  "The  Diseases  of  Infancy  and  Childhood,"  New  York,  1897,  p.  806. 

3  Boston  Med.  and  Surg.  Jour.,  1894,  vol.  exxxi,  p.  133. 

4  Arch.  Pediat.,  1898,  vol.  xv,  p.  330. 

5  Munch,  med.  Wochenschr.,  1898,  vol.  xlv,  p.  44. 


349 


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350 


ANEMIA  IN  CHILDREN. 


351 


seen  a  case  of  myelogenous  leukemia  in  a  new-born  infant,  the 
count  on  the  fourteenth  day  after  birth  being  2,500,000  erythro- 
cytes and  312,500  leucocytes  per  c.mm.  The  latter  consisted 
chiefly  of  "large  mononucleated  cells,  with  large,  distinct  nuclei 
and  an  abundance  of  protoplasm."  Nucleated  forms  of  ery- 
throcytes were  not  found.  Cassel,1  in  addition  to  his  own  case, 
tabulated  above,  has  collected  four  others  occurring  in  children 
under  fourteen  years  of  age. 

Theodor2  has  collected  from  German  literature  six  cases  of 
acute  leukemia  in  children  between  the  ages  of  two  and  one-half 
and  eight  years  of  age,  and  also  reports  one  of  his  own,  apparently 
of  the  lymphatic  form,  in  a  boy  of  four  years.  No  actual  numer- 
ical estimates  of  the  corpuscles  are  given,  but  the  proportion  of 
leucocytes  to  erythrocytes  is  stated  to  vary  from  1  : 9  to  1  : 3.  The 
differential  count  of  leucocytes  is  also  very  inexact.  The  greater 
percentage  apparently  consisted  of  lymphocytes;  myelocytes  were 
fairly  numerous,  many  of  them  containing  mitotic  figures,  and 
normoblasts  and  megaloblasts  were  present  in  large  numbers. 
Gilbert  and  Weil,3  in  1899,  published  data  of  five  acute  lymphatic 
cases  in  children  between  the  first  and  tenth  years.  Charon  and 
Gratea4  report  a  case  of  myelogenous  leukemia  in  a  child  of  eight 
years,  the  percentage  of  hemoglobin  being  39,  the  erythrocyte 
count  880,000,  and  the  leucocyte  count  305,000.  Instances  of 
acute  lymphatic  leukemia  in  children  have  also  been  reported, 
with  more  or  less  accuracy,  by  Bradford  and  Shaw,5  by  Guinon 
and  Jolly,6  by  Haushalter  and  Richon,7  and  by  Bloch  and 
Hirschfeld.8 

In  the  above  classification  of  the  secondary 
Secondary    anemias,  under  the  heading  of  mild  anemia  are 
Anemia.      included  those  cases  characterized  by  trifling  re- 
duction in  the  hemoglobin  percentage  and  num- 
ber of  erythrocytes,  and  by  an  absence  of  histological  alterations 
in  these  cells.    The  color  index  in  these  cases  is  usually  1.00,  or 
slightly  below,  uncommonly  falling  to  a  low  figure. 

The  term  severe  anemia  includes  cases  having  marked  diminu- 
tion of  hemoglobin  and  erythrocytes,  associated  with  deformities 
of  shape  and  of  size  and  nucleation  of  these  cells.    The  hemo- 

1  Berlin,  klin.  Wochenschr.,  1898,  vol.  xxxv,  p.  76. 

2  Arch.  f.  Kinderheilk.,  1897,  vol.  xxii,  p.  47. 

3  Arch,  de  med.  exper.,  1899,  vol.  ii,  p.  157. 

4  Bull.  Soc.  roy.  sc.  med.  et  nat.,  Brussels,  1896,  vol.  liv,  p.  63. 

5  Trans.  Roy.  Med.-chir.  Soc,  1898,  vol.  lxxxi,  p.  343. 

6  Rev.  mens,  des  mal.  de  l'Enf.,  1899,  vol.  i,  p.  262. 

7  Arch,  de  med.  des  Enf.,  1899,  vol.  ii,  p.  356. 

8  Zeitschr.  f.  klin.  Med.,  1900,  vol.  xxxix,  p.  32. 


352 


THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 


globin  loss  is  especially  marked,  often  being  only  one-quarter  or 
one-third  of  normal,  and  the  color  index  is  low. 

Anemias  with  leucocytosis,  whether  of  mild  or  of  severe  type, 
are  generally  marked  by  a  greater  degree  of  hemoglobin  and 
corpuscular  decrease  than  anemias  without  leucocytosis.  The 
leucocytosis  is  moderate  in  the  milder  forms,  but  in  severe  cases 
the  increase  in  the  number  of  leucocytes  often  appears  to  be  pro- 
gressive, and  the  relative  number  of  leucocytes  to  erythrocytes 
occasionally  attains  the  proportion  of  i  to  100. 

Histological  changes  in  the  erythrocytes  are  more  striking  in 
grave  anemias  with  leucocytosis  than  in  grave  anemias  pure  and 
simple.  This  is  especially  true  of  the  changes  relating  to  nuclea- 
tion  of  the  cells,  normoblasts  and  atypical  forms  being  very  nu- 
merous in  the  former  class.  As  already  stated,  megaloblasts  do 
not  necessarily  mean  a  fatal  nor  even  an  especially  intense  anemia. 

Regarding  the  etiological  factors  of  these  secondary  anemias, 
.the  following  groups  of  causes  are  given  by  Monti 

1.  Congenital   Syphilis,  tuberculosis,  and  other  infections. 

Hemorrhagic.      I  From  navel,  from  circumcision,  etc. 
j  Purpuric  diseases. 
I  Malnutrition,  improper  hygiene,  etc. 
j  Syphilis,  rachitis,  and  tuberculosis. 

2.  Acquired   /  G astro-intestinal  diseases. 

\  Visceral  diseases. 
General.  j  Febrile  diseases. 

/  Septic  infections. 

\  Nephritides. 

\  Malignant  growths. 

Syphilis,  either  congenital  or  acquired,  is  responsible  for  a 
large  proportion  of  the  cases  of  anemia  in  children,  especially  those 
of  a  severe  type,  associated  with  enlargement  of  the  spleen,  and 
often  also  with  enlargement  of  the  lymphatic  glands.  The  hemo- 
globin loss  is  in  most  instances  disproportionately  greater  than  the 
corpuscular  decrease,  so  that  low  color  indices  are  especially 
common  in  this  disease — the  misnamed  "chlorosis"  of  syphilis. 
Deformities  and  nucleation  of  the  erythrocytes  are  common  in 
the  severer  types,  and  in  such  forms  polychromatophilic  changes 
and  excessive  decrease  in  the  number  of  erythrocytes  are  usually 
present.  A  leucocyte  increase  is  present  in  the  secondary  stage, 
and  is  usually  associated  with  the  grave  anemia  of  this  disease; 
the  relative  percentage  of  lymphocytes  is  increased,  and  of  poly- 
morphous forms  decreased;  and  small  numbers  of  myelocytes 
are  common.  From  the  writer's  experience,  in  the  average  case 
of  moderate  severity  the  percentage  of  hemoglobin  varies  from 

1  Wien.  med.  Wochenschr.,  1894,  vol.  xliv,  pp.  401,  464,  516,  560,  and  613. 


ANEMIA  IN  CHILDREN. 


353 


about  40  to  50,  the  erythrocytes  are  reduced  to  about  3,000,000  to 
3,500,000  per  c.mm.,  and  the  leucocyte  count  is  in  the  neighbor- 
hood of  20,000;  but  in  severe  cases  the  erythrocytes  may  be  re- 
duced to  1,000,000,  and  the  leucocytes  increased  to  50,000  or 
more.  As  in  the  adult,  Justus'  test  proves  of  value  in  the  diagnosis 
of  many  anomalous  cases.  Labbe  and  Armand  Delille 1  insist  that 
in  congenital  syphilis  the  blood  picture  may  precisely  resemble 
that  of  von  Jaksch's  disease  (q.  v.),  but  that  the  blood  promptly 
returns  to  normal  after  energetic  mercurialization. 

In  rachitis  there  is  usually  well-marked  anemia,  accompanied 
by  decided  enlargement  of  the  spleen,  such  cases  having  most 
decided  blood  changes.  The  hemoglobin  percentage  tends  to 
range  lower  than  the  percentage  of  corpuscles,  so  that  low  color 
indices  prevail;  but  in  the  individual  case  neither  the  oligo- 
chromemia  nor  the  oligocythemia  is  generally  as  marked  as  in 
syphilis.  In  severe  .cases,  deformed  and  nucleated  erythrocytes 
and  a  small  percentage  of  myelocytes  are  commonly  found.  The 
number  of  leucocytes  is,  as  a  rule,  moderately  increased,  and 
relatively  high  percentages  of  lymphocytes  are  common. 

Uncomplicated  tuberculosis,  due  to  pure  infections  with  the 
tubercle  bacillus,  produces  an  anemia  which  varies  in  degree 
with  the  severity  of  the  constitutional  effects  of  the  disease.  The 
hemoglobin  and  erythrocytes  are  usually  but  slightly  decreased, 
the  former  suffering  a  relatively  greater  loss,  and  the  number  of 
leucocytes  does  not  rise  above  normal.  If  to  the  tuberculous 
process  a  septic  infection  is  superadded,  the  anemia  becomes 
severer,  and  leucocytosis,  involving  the  polymorphous  forms  of 
cells,  occurs.  Splenic  enlargement  is  common  and,  sometimes 
marked.  The  anemia  of  tuberculosis  is  in  no  way  referable  to 
the  infection  itself,  but  depends  upon  the  drain  on  the  albumins 
of  the  blood  due  to  the  presence  of  a  long- continued  cachexia 
and  upon  secondary  infections. 

G astro-intestinal  diseases,  especially  those  of  chronic  character, 
cause  most  marked  anemia.  Chronic  inflammations  of  the  intes- 
tines strikingly  affect  the  blood,  the  percentage  of  hemoglobin 
frequently  falling  to  one- quarter  of  normal  or  even  lower,  and  the 
number  of  erythrocytes  being  decreased  to  one-half  of  normal  or 
lower.  Deformities  affecting  the  shape  and  size  of  the  erythrocytes 
and  nucleation  of  these  cells  are  of  frequent  occurrence.  A  leu- 
cocyte increase,  involving  in  many  instances  the  lymphocytes, 
is  usually  present,  and  small  percentages  of  myelocytes  have 
been  observed.  Splenic  enlargement  is  frequently  a  conspicu- 
ous clinical  sign.    It  should  be  remembered  that  in  acute  forms 

1  Sem.  med.,  1903,  vol.  xxiii,  p.  50. 

23 


354 


THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 


of  gastro-intestinal  disorders,  in  which  profuse  diarrhea  and  vom- 
iting occur,  concentration  of  the  blood  takes  place,  causing  tem- 
porary polycythemia  which  may  for  a  time  hide  the  real  degree 
of  the  blood  deterioration.  The  anemias  found  in  this  class  of 
diseases  are  apparently  to  a  large  extent  autointoxicativc  in  char- 
acter, depending  to  a  less  degree  upon  insufficient  nutrition. 

In  enteric  fever  the  blood  picture  does  not  differ  essentially 
from  that  seen  in  the  adult  suffering  from  this  affection,  absence 
of  leucocytosis  or  leucopenia  with  progressive  anemia  being 
found  with  great  constancy.  The  difference  is  simply  one  of 
degree,  the  changes  developing  more  rapidly  but  persisting  for  a 
shorter  period  in  the  child  than  in  the  adult.  Churchill's  studies  1 
show  that  the  leucopenia  is  most  decided  during  the  second  week 
of  the  fever;  and  that  the  anemia  is  especially  apparent  during  the 
first  three  weeks;,  after  which  the  hemoglobin  and  erythrocytes 
begin  steadily  to  increase,  reaching  normal  by  about  the  fifth 
week.  In  12  cases  studied  by  Stengel  and  White 2  the  hemoglobin 
ranged  from  68  to  83  per  cent.,  the  erythrocytes  from  3,320,000  to 
5,200,000,  and  the  leucocytes  (in  uncomplicated  cases)  from  3800 
to  12,320.  Polynuclear  leucocytosis  was  observed  in  3  cases  as  the 
result  of  inflammatory  complications.  Two  uncomplicated  cases 
showed  fractional  percentages  of  myelocytes,  but  there  were  no 
other  differential  changes  of  any  consequence.  Head 3  believes  that 
in  uncomplicated  cases  the  leucocytes  never  number  more  than 
10,000  per  c.mm.  The  writer  has  found  that  the  alkalinity  of  the 
blood  varies  within  wide  limits  in  infantile  typhoid,  tests  by 
Engel's  method  in  6  consecutive  cases  showing  a  range  of  from 
373  to  692  mgm.  NaOH.  The  rapidity  of  coagulation  also  was 
found  to  vary  greatly,  clotting  taking  place  in  as  short  a  time  as 
thirty-seven  seconds  in  one  instance,  and  not  occurring  for  four 
minutes  and  thirty-five  seconds  in  another.  Morse 4  concludes 
that  the  serum  test  appears  earlier,  is  less  marked,  and  persists  for 
a  shorter  period  in  children  than  in  adults.  In  a  nursling  it 
should  be  remembered  that  a  positive  reaction  may  be  of  uncertain 
value,  for  the  reason  that  the  agglutinating  power  may  be  trans- 
mitted from  mother  to  child  through  the  milk,  both  during  the 
active  stages  of  the  disease  and  also  during  and  after  convales- 
cence. 

Under  the  title  " anemia  infantum  pseudoleukemica"  von 
Jaksch 5  has  described  a  condition  which  he  regards  as  a  form  of 

1  Boston  Med.  and  Surg.  Jour.,  1903,  vol.  clviii,  p.  692. 

2  Arch.  Pediat.,  1901,  vol.  xviii,  pp.  241  and  321. 

3  Ibid.,  1902,  vol.  xix,  p.  253.  4  Ibid.,  1901,  vol.  xviii,  p.  338. 
5  Wien.  klin.  Wochenschr.,  1889,  vol.  ii,  p.  435. 


ANEMIA  IN  CHILDREN. 


355 


primary  anemia  peculiar  to  the  young  child.  The  blood  changes, 
which  are  not  characteristic  of  the  disease  in  question,  as  this 
author  admits,  consist  of  (a)  marked  oligocythemia  and  oligo- 
chromemia;  (b)  extensive  and  persistent  leucocyte  increase;  and 
(c)  striking  structural  alterations  in  the  erythrocytes.  Associated 
with  these  changes  in  the  blood,  and  of  equal  importance  in  diag- 
nosing the  disease;  constant  enlargement  of  the  spleen  and,  less 
commonly,  enlargement  of  the  liver  are  found. 

The  number  of  erythrocytes  is  greatly  decreased,  usually ^  to 
from  2,000,000  to  3,000,000  per  c.mm.,  but  sometimes  falling 
to  1,000,000  or  even  to  a  lower  figure,  as  in  one  of  von  Jaksch's 
cases,  in  which  the  count  was  only  820,000.  The  hemoglobin 
loss  is  also  great — relatively  more  so  than  the  corpuscular  decrease. 

The  leucocyte  gain  is  decided,  averaging,  in  the  majority  of 
cases,  from  30,000  to  50,000  corpuscles  per  c.mm.,  and  in  some 
instances  exceeding  100,000.  In  some  cases  the  increase  involves 
principally  the  polynuclear  neutrophiles,  while  in  others  the  lym- 
phocytes are  the  cells  chiefly  affected.  The  cells  show  a  most 
striking  dissimilarity  of  form  and  of  size,  and  a  highly  confusing 
variety  of  forms  atypical  in  size,  shape,  and  nuclear  morphology 
is  encountered.  This  "polymorphous"  state  of  the  leucocytes 
is  a  point  insisted  upon  by  von  Jaksch  in  his  description  of  the 
condition.  The  number  of  eosinophiles  varies  within  wide 
limits,  the  percentage  of  these  cells  being  normal,  decreased,  or 
increased.    Small  percentages  of  myelocytes  have  been  observed. 

The  histological  changes  affecting  the  erythrocytes  consist  in 
marked  poikilocytosis,  deformities  of  size,  loss  of  color,  and  nu- 
cleation.  Poikilocytes,  megalocytes,  and  microcytes  occur  in 
large  numbers,  and  the  pallor  of  most  of  the  corpuscles  is  ex- 
treme. Normoblasts  are  the  most  common  form  of  erythro- 
blasts  observed,  but  occasionally  the  occurrence  of  atypical  forms, 
small  and  large,  and  of  megaloblasts  has  been  noted.  Karyokin- 
etic  changes  in  these  cells  are  not  uncommonly  seen,  and  poly- 
chromatophilia  is  of  frequent  occurrence. 

The  spleen  is  enlarged  in  all  cases,  sometimes  moderately,  but 
often  very  greatly,  so  that  the  organ  extends  far  below  the  cos- 
tal margin,  and  occupies  the  entire  upper  left  part  of  the  abdomi- 
nal cavity.  The  spleen  is  extremely  indurated,  and  may  show 
capsular  thickening  from  perisplenitis.  The  increase  in  the  size 
of  the  organ  is  due  to  a  hyperplasia.  Enlargement  of  the  liver 
is  not  constant  in  all  cases,  and  when  present  does  not  reach  a 
size  corresponding  to  that  of  the  spleen,  as  is  the  case  in  leukemia; 
the  lower  border  of  the  liver  is  not  rounded,  but  distinctly  sharp. 
In  a  certain  proportion  of  cases  the  lymphatic  glands  are  slightly 


356  THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 

enlarged,  but  never  to  any  notable  extent.  Changes  in  the  bone 
marrow,  common  to  any  severe  anemia,  have  been  observed  in 
some  cases. 

The  disease  occurs  most  frequently  in  infants  between  the  ages 
of  seven  and  twelve  months,  and  is  rarely  met  with  in  children 
over  four  years  old.  By  some  writers  it  is  supposed  to  be  slightly 
more  common  in  children  of  the  male  sex. 

In  many  cases  a  previous  history  of  rachitis,  syphilis,  or  long- 
standing gastro-intestinal  disease  is  obtained,  although  von 
Jaksch  denies  the  existence  of  these  etiological  factors  in  his  cases. 

The  onset  of  the  symptoms  is  slow  and  insidious,  and  the  pal- 
lor of  the  skin,  blanching  of  the  mucous  membranes,  and  other 
signs  of  anemia  slowly  develop,  with  the  gradual  enlargement  of 
the  spleen,  until  these  clinical  manifestations  become  marked. 
In  all  cases  there  is  excessive  loss  of  strength,  and  in  a  great 
many  a  high  degree  of  emaciation. 

Von  Jaksch's  disease,  if  untreated,  tends  to  pursue  a  progres- 
sively grave  course,  ending  fatally;  but,  under  suitable  treatment, 
the  splenic  tumor  decreases  in  size,  the  leucocytosis  disappears 
and  the  hemoglobin  and  erythrocytes  return  to  normal. 

Pseudoleukemic  anemia  of  infants  is  not  generally  considered 
as  a  separate  clinical  entity,  but  is  regarded  rather  as  a  form  of 
severe  secondary  anemia  associated  with  marked  leucocytosis  and 
splenic  enlargement.  It  may  be  due  to  a  number  of  different 
causes,  the  most  prominent  among  which  are  syphilis,  rachitis, 
and  chronic  gastro-intestinal  disease.  The  conflicting  reports  of 
different  authors  concerning  this  disease,  and  the  incompleteness 
with  which  the  leucocytes  have  been  studied  in  many  instances, 
render  it  probable  that  in  some  of  the  reported  cases  pernicious 
anemia  and  leukemia  have  masqueraded  as  typical  examples  of 
the  condition  described  by  von  Jaksch. 

Bacteriemia,  generally  referable  to  preagonal  infections, 
appears  to  occur  with  great  frequency  in  the  young  child  during 
the  course  of  many  acute  diseases.  Delestre's  careful  studies 1  of 
general  blood  infections  in  children  tend  to  show  that  infants  born 
before  full  term  are  peculiarly  susceptible  to  this  condition.  Using 
careful  technic,  this  author  examined  40  children,  ranging  in  age 
from  a  few  days  to  four  years,  all  of  whom  were  believed  to  be 
suffering  from  infections  which  bade  fair  to  end  fatally  within  a 
few  days,  at  the  latest.  Of  the  32  fatal  cases  of  this  series,  bacteria 
were  found  in  the  blood  during  life  in  14,  while  of  the  8  who  re- 
covered, but  one  gave  a  positive  result.  The  bacterium  found 
with  greatest  frequency  was  the  streptococcus,  while  staphylococci, 

1  Annal.  de  gynecol.  et  d'obstet.,  1901,  vol.  Iv,  p.  51. 


ANEMIA  IN  CHILDREN. 


357 


pneumococci,  colon  bacilli,  and  influenza  bacilli  were  isolated  more 
rarely.  It  was  furthermore  shown  that  premature  babies  seemed 
especially  susceptible  to  streptococcus  and  colon  infections,  and 
that  nursing  infants  several  months  old  were  more  prone  to  suffer 
from  the  effects  of  the  staphylococcus. 

The  blood  changes  occurring  in  pertussis,  pneumonia,  diph- 
theria, scarlet  fever,  measles,  varicella,  and  other  infectious  diseases 
of  childhood  are  considered  in  Section  VII. 


- 


SECTION  VII. 


GENERAL  HEMATOLOGY. 


SECTION  VII. 
GENERAL  HEMATOLOGY. 


I.  ABSCESS. 

The  rate  of  coagulation  is,  as  a  rule,  somewhat 
General      slower  than  normal.    Hyperinosis  is  conspicuous, 
Features.     and  under  the  microscope  the  fibrin  network  ap- 
pears abnormally  dense  and  thick.    The  iodin 
reaction  may  be  detected  in  the  dried  blood  film  by  the  method 
described  in  a  previous  section.    (See  p.  226.)    These  remarks, 
as  well  as  those  which  follow,  do  not  apply  to  purely  tuberculous  or 
"cold"  abscesses,  the  effects  of  which  are  referred  to  elsewhere. 

If  the  absorption  of  toxic  material  from  an  ab- 
Hemoglobin    scess  is  great  enough  to  produce  a  systemic  effect 
and         upon  the  patient,  anemia  of  an  intensity  parallel 
Erythrocytes,  to  the  severity  of  the  poisoning  sooner  or  later 
develops.    This  fact  is  sufficient  to  explain  why 
the  grades  of  anemia  in  purulent  conditions  vary  within  such  wide 
limits.    The  size  and  the  site  of  the  abscess  do  not  appear  pri- 
marily to  determine  the  degree  of  the  associated  blood  changes, 
although,  other  circumstances  being  equal,  a  large,  deep-seated 
collection  of  pus  is  likely  to  have  a  more  harmful  effect  than  one 
of  small  size  and  superficial  situation.    Chronicity  of  the  lesion 
seems  to  go  hand  in  hand  with  an  increase  in  the  blood  deterio- 
ration— few  persons  harboring  pus  for  a  protracted  period  fail  to 
show  decided  signs  of  anemia. 

In  many  cases,  especially  the  acute,  the  only  noticeable  change 
is  a  moderate  oligochromemia,  but  in  chronic  cases  different  de- 
grees of  ordinary  secondary  anemia  are  commonly  encountered, 
amounting  in  an  exceptional  instance  to  a  reduction  of  hemo- 
globin to  as  low  as  20  or  30  per  cent,  of  the  normal  standard,  and 
to  an  erythrocyte  decrease  to  between  2,000,000  and  3,000,000 
cells  to  the  c.mm.  Such  profound  losses  are,  of  course,  unusual, 
for  in  the  majority  of  patients  with  anemia  the  hemoglobin  is 
above  50,  and  the  corpuscles  above  60,  per  cent,  of  normal.  The 
average  color  index  for  134  German  Hospital  cases,  listed  below, 


362 


GENERAL  HEMATOLOGY. 


was  0.77.  The  condition  of  the  hemoglobin  and  erythrocytes 
in  these  patients  is  shown  by  the  following  summary: 

Erythrocytic  Number  of 

Per  c.mm.  Cases. 

Above  5,000,000  in..  10 

From   4,000,000-5,000,000  "  .  .41 

"      3,000,000-4,000,000  "  ..68 

"      2,000,000-3,000,000  "  . .  9 

"      1,000,000-2,000,000  "  . .  6 


Average,     3,797,470  per  c.mm. 
Maximum,  5,970,000   "  " 
Minimum,  1,320,000   "  " 

If  marked  anemia  exists,  a  variable  grade  of  cell  deformity, 
atypical  staining,  and  nucleation  is  also  to  be  observed.  If  the 
latter  change  is  evident,  it  will  be  found  that  the  great  majority,  if 
not  all,  of  the  nucleated  corpuscles  belong  to  the  normoblastic  class. 

Practically  the  same  influences  governing  the 
Leucocytes,  behavior  of  the  leucocytes  in  most  other  infec- 
tions also  determine  their  increase  and  decrease 
in  abscess.  Thus,  in  both  trivial  and  in  extensive  pus  foci  the 
number  of  leucocytes  may  be  normal  or  even  subnormal;  in  the 
former  instance  because  systemic  reaction  is  not  provoked,  and 
in  the  latter  because  it  is  overpowered.  Leucocytosis  may  also 
be  absent  in  case  toxic  absorption  is  impossible,  owing  to  the  com- 
plete walling-off  of  the  abscess.  kIn  all  other  instances  save  these 
a  definite  and  usually  well-marked  leucocytosis  occurs,  amount- 
ing on  the  average  to  a  count  of  about  twice  the  mean  normal 
standard,  but  often  greatly  exceeding  this  figure  in  the  individual 
case.  The  size  of  the  primary  abscess  cannot  be  estimated  by 
the  height  of  the  leucocytosis,  but  a  tendency  of  the  pus  to  extend 
is  almost  always  accompanied  by  a  distinct  increase  in  the  number 
of  cells  in  excess  of  the  figure  originally  estimated.  Complete  evac- 
uation of  the  abscess  is  soon  followed  by  a  disappearance  of  the 
leucocytosis  and  iodophilia,  but  so  long  as  the  pus  remains  inef- 
fectually drained,  these  signs  persist. 

Analysis  of  the  "first  counts"  in  258  cases  of  various  forms  of 
abscess  (excluding  appendicitis)  shows  that  in  184,  or  71.3  per 
cent.,  the  leucocyte  count  was  in  excess  of  10,000.  The  general 
range  of  the  leucocytes  in  abscess  is  illustrated  by  the  following 
table: 


Hemoglobin  Number  of 
Percentage.  Cases. 

From  90- loo  in   4 

"    80-90     "   15 

"    70-80    "  .  27  • 

"    60-70    "   23 

"    50-60    "   23 

"    40-50     "   22 

"    3°"40    "   13 

>   "    20-30    «    7 

Average,     59  per  cent. 

Maximum,  95  " 

Minimum,  20  'f* 


ABSCESS. 


363 


Leucocytes  per  c.mm.                          Number  of  Cases. 
40,000-50,000   2 

30,000-40,000   5 

20,000-30,000  28 

15,000-20,000  59 

10,000-15,000  9° 

5,000-10,000  7° 

Below  5000   4 

Average,  13,931  per  c.mm. 
Highest,  42,000 
Lowest,       550  " 

A  more  detailed  study  of  these  cases,  directed  toward  the 
number  of  the  leucocytes  in  relation  to  the  site  of  the  abscess,  may 
be  expressed  thus  in  tabular  form: 


Site  of  Abscess. 

Cases. 

Average. 

Highest. 

Lowest. 

Cases  with  Leukocytosis. 

Pelvic  

164 

13.837 

42,000 

55° 

107  or 

66.9 

per  cent. 

Kidney  

3°II3>924 

33,600 

6,000 

26  " 

86.6 

tc 
it 

Superficial  

26 

13,168 

24,000 

4,800 

19  « 

73-° 

tt 

Empyema  

10  17,180 

31,800 

11,200 

10  " 

100.0 

tt 

Lung  

8 

12,128 

I7>650 

8,200 

6  " 

75-° 

Liver  

8 

14,922 

23,400 

9.300 

6  " 

75-° 

tt 

Gall-bladder  . . . 

6 

!i5>65° 

21,200 

;  9*50° 

5  " 

83-3 

it 

6 

! 1 3  >4°6 

1 

18,560 

1  6,800 

1 

5  " 

83-3 

it 

A  polynuclear  neutrophile  gain  generally  accounts  for  the 
increase  when  leucocytosis  is  present,  and,  rarely,  this  differential 
change  may  be  found  without  any  increase  in  the  total  number  of 
cells.  In  some  instances,  and  these  are  not  so  uncommon  as 
is  generally  believed,  the  increase  affects  all  forms  of  cells  pro- 
portionately. A  few  myelocytes  are  not  uncommon  in  cases  having 
a  decided  anemia  or  a  high  leucocytosis. 

The  presence  of  leucocytosis,  especially  if 

Diagnosis,    associated  with  hyperinosis  and  a  positive  iodin 
reaction,  is  suggestive  of  abscess  rather  than  of 
other  lesions,  such  as  aneurisms,  gummata,  hematomata,  and 
benign  neoplasms.    An  absence  of  one  or  all  of  these  signs,  on  the 
other  hand,  is  not  sufficient  to  exclude  pus.    The  distinctions,  as 


364 


GENERAL  HEMATOLOGY. 


shown  by  the  blood,  between  pyogenic  and  tuberculous  abscesses 
and  malignant  disease  are  considered  under  the  last-named  con- 
ditions. 

II.  ACROMEGALY. 
The  following  counts  illustrate  the  blood  changes  found  in  two 
cases  of  this  disease,  the  first  showing  practically  normal  blood, 
except  for  a  moderate  relative  lymphocytosis  and  an  absence  of 
eosinophiles,  and  the  second  simply  a  well-marked  secondary 
anemia  with  a  high  color  index. 

Hemoglobin  

Color  index  

Erythrocytes  '  

Leucocytes  

Small  lymphocytes  

Large  lymphocytes  

Polynuclear  neutrophiles 

Eosinophiles  

Basophiles  

Myelocytes  

The  erythrocytes  showed  moderate  deformities  of  size  and 
shape  in  the  anemic  case,  but  no  signs  of  nucleation  nor  of  baso- 
philic stroma  degeneration  were  observed.  Coagulation,  fibrin 
formation,  and  the  number  of  plaques  were  apparently  normal. 


III.  ACTINOMYCOSIS. 

Anemia,  marked  by  a  disproportionately  great  hemoglobin  de- 
crease, is  sometimes  found,  and  leucocytosis  appears  to  be  an 
almost  constant  change,  judging  from  the  small  number  of  reports 
available.  In  a  case  of  actinomycosis  of  the  arm  the  writer  found 
55  per  cent,  of  hemoglobin,  with  4,985,000  erythrocytes  and  12,000 
leucocytes  per  c.mm.  The  number  of  blood  plaques  was  greatly 
increased  and  the  erythrocytes  were  pale,  but  not  deformed, 
nucleated,  nor  basophilic.  The  percentages  of  the  leucocytes 
were:  small  lymphocytes,  25.5;  large  lymphocytes,  7.3;  polynuclear 
neutrophiles,  60.0;  eosinophiles,  2.4;  myelocytes,  3.2;  basophiles 
(finely  granular),  1.0;  and  mast  cells,  0.6. 


Case  I. 
.  86  per  cent. 

°-93 
.4,620,000  per 
c.mm. 
8,000  per 
c.mm. 
.31.7  per  cent. 
.  2.1 
.66.2 
.  0.0 
,  0.0 
.  0.0 


Case  II. 
60  per  cent. 

1.04 
2,880,000  per 
c.mm. 
4,890  per 
c.mm. 
21.0  per  cent. 
7.0 
71.0 
1.0 
0.0 
0.0 


ADDISON  S  DISEASE. 


Erving1  reports  4  cases  with  leucocyte  counts  of  10,000,  12,000, 
21,000,  and  36,200;  Ewing's  case2  gave  21,500;  and  Cabot's  two2 
showed  leucocytoses  of'  from  20,000  to  31,700.  As  a  rule,  actin- 
omycosis excites  a  higher  leucocytosis  when  deep  organs  (liver, 
lungs)  are  involved  than  when  the  lesion  is  situated  in  superficial 
parts  of  the  body  (jaw,  elbow,  abdominal  wall)  where  free  drainage 
is  favored.  It  is  probable  that  the  grade  of  both  the  anemia  and 
the  leucocytosis  depends  largely  upon  the  amount  of  septic  ab- 
sorption originating  from  the  lesion. 


IV.  ACUTE  YELLOW  ATROPHY  OF  THE  LIVER. 

Malignant  jaundice  appears  to  be  associated  with  a  moderate 
polycythemia,  so  far  as  can  be  determined  by  the  limited  number 
of  blood  counts  made  in  this  disease  up  to  the  present  time.  The 
leucocytes  are  moderately  increased  in  number,  but  show  no 
peculiar  differential  changes.  In  two  cases,  reported  by  Grawitz 3 
and  by  Cabot,4  respectively,  the  counts  of  erythrocytes  were 
5,150,000  and  5,520,000,  and  the  number  of  leucocytes  12,000 
and  16,000  per  c.mm.  Bacteriological  examination  of  the  blood 
has  thrown  no  definite  light  upon  the  nature  of  this  apparently 
infectious  process.  In  many  cases  hemoglobinemia  and  lipaci- 
demia  have  been  detected. 

V.  ADDISON'S  DISEASE. 
Moderate  anemia  is  commonly,  and  decided 
Hemoglobin  anemia  occasionally,  associated  with  this  condi- 
AND         tion,  although  the  prime  importance  of  this 
Erythrocytes,  symptom  insisted  upon  by  Addison  himself  ap- 
pears to  be  somewhat  exaggerated,  in  the  light 
of  our  more  accurate  methods  of  blood  study.    The  "anemiated 
eye"  of  Addison  does  not  always  mean  anemia.    In  advanced 
cases  the  blood  picture  may  be  characterized  by  marked  hemo- 
globin and  erythrocyte  losses,  by  the  presence  of  numerous  poikil- 
ocytes  and  microcytes,  and  by  small  numbers  of  normoblasts; 
the  hemoglobin  readings  in  such  instances  range  between  20  and 
40  per  cent.,  and  the  erythrocyte  counts  between  2,000,000  and 
3,000,000  per  c.mm.,  or  even  less.    Tschirkoff 5  reports  cases  in 
which,  notwithstanding  the  coexistence  of  a  notable  oligocythe- 

1  Johns  Hopkins  Hosp.  Bull.,  1902,  vol.  xiii,  p.  261. 

2  Loc.  cit.  8  Loc.  cit. 

i  Loc.  cit.  5  Zeitschr.  f.'klin.  Med.,  1890,  vol.  xix,  p.  87. 


366 


GENERAL  HEMATOLOGY. 


mia,  the  hemoglobin  percentage  remained  normal  or  above  nor- 
mal, and  this  peculiar  condition  he  referred  to  an  increase  in  the 
amount  of  corpuscular  reduced  hemoglobin.  This  author  also 
detected  the  presence  of  methemoglobin  and  melanin  in  the  blood 
of  patients  suffering  from  Addison's  disease.  The  polycythemia 
which  is  sometimes  met  with  in  this  condition  is  doubtless  to 
be  attributed  to  such  factors  as  vasomotor  changes  and  blood 
inspissation  from  emesis.  Treatment  with  suprarenal  extract 
tends  to  improve  the  anemia,  but  to  what  extent  and  how  per- 
manently is  undetermined. 

The  number  of  leucocytes  is  usually  normal 
Leucocytes,  or  below  normal,  and  extreme  leucopenia  has 
been  repeatedly  noted.    Relative  lymphocytosis 
and  sometimes  a  moderate  increase  in  the  number  of  eosinophiles 
are  the  most  familiar  differential  changes,  together,  in  some  in- 
stances, with  the  presence  of  a  few  myelocytes  and  basophiles. 

VI.  ANTHRAX. 

Nothing  definite,  is  known  of  the  behavior  of  the  hemoglobin 
and  corpuscles  in  this  infection.  Only  occasionally  can  the  anthrax 
bacillus  be  isolated  from  the  peripheral  blood,  since  general  inva- 
sion of  the  circulation  by  this  organism  is  rare.  Blumer  and 
Young 1  succeeded  in  finding  the  organism  in  the  blood  of  a  single 
case  of  anthrax  septicemia,  both  in  ordinary  cover-glass  speci- 
mens as  well  as  by  culturing. 


VII.  APPENDICITIS. 

Fully  three-fourths  of  all  cases  of  appen- 
Hemoglobin  dicitis,  whatever  their  character,  show  a  loss  of 
AND         at  least  30  per  cent,  of  hemoglobin,  while  in 
Erythrocytes,  about  one  case  in  five  the  erythrocytes  are  di- 
minished 1,000,000  or  more  to  the  c.mm.  From 
an  analysis  of  the  cases  tabulated  below  it  appears  that  the  average 
hemoglobin  loss  amounts  to  about  25  per  cent.,  and  the  average 
decrease  in  erythrocytes  to  about  15  per  cent,  of  the  normal 
standard.    The  anemia,  which  may  usually  be  attributed  to  the 
effects  of  septicemia,  is  most  frequent  and  most  marked  in  long- 
standing cases  of  appendicular  abscess,  in  which  type  of  the  dis- 
ease the  hemoglobin  may  fall  to  between  30  and  40  per  cent., 
and  the  corpuscles  to  between  2,000,000  and  3,000,000  per  c.mm. 

1  Johns  Hopkins  Hosp.  Bull.  1895,  vol.  vi,  p.  127. 


APPENDICITIS. 


In  such  instances  the  risk,  actual  or  reputed,  of  operating  upon  a 
patient  having  so  low  a  percentage  of  hemoglobin  must  be  re- 
called by  the  surgeon.  (See  p.  164.)  Anemia,  usually  of  a  more 
moderate  grade,  is  also  frequently  found  in  catarrhal  cases,  and 
in  the  individual  instance  it  may  reach  as  high  a  grade  as  in  the 
purulent  form  of  the  disease.  The  blood  impoverishment  in  such 
instances  depends  probably  upon  the  debilitated  state  of  the  pa- 
tient, apart  from  the  appendix  inflammation. 

The  following  table  illustrates  the  range  of  the  hemoglobin  and 
erythrocytes,  as  shown  by  the  initial  examinations  of  139  cases1 
in  Dr.  J.  B.  Deaver's  wards  at  the  German  Hospital: 

Number  op  Cases. 


Hemoglobin  Percentage.  Non-purulent. 

Above  100   1 

From  90-100   1 

"    80-90   9 

"    70-80   13 

"    60-70   13 

"    50-60   6 

"    40-50   2 

"    30-40  -   o 

Highest  102  per  cent. 

Lowest   45 

Average   69.5 

Erythrocytes  per  c.mm. 

Above  5,000,000   6 

From  4,000,000-5,000,000   27 

"    3,000,000-4,000,000   11 

"     2,000,000-3,000,000.   1 

Highest  5,660,000  per 

c.mm. 

Lowest  2,050,000  per 

c.mm. 

Average  4,295,955  per 

c.mm. 


Purulent,  Perfora- 
tive, and  Gan- 
grenous. 

O 

4 
20 

31 
23 

7 

6 

3 

100  per  cent. 
38  " 
72.5  " 


14 
60 

15 
5 

5,710,000  per 

c.mm. 
2,100,000  per 

c.mm. 
4,381,234  per 

c.mm. 


Qualitative  changes  in  the  erythrocytes  are  neither  common 
nor  important,  occurring  only  in  cases  with  decided  anemia,  and 
consisting  simply  in  deformities  of  shape  and  of  size.  Erythro- 

1  Similar  figures  were  found  in  the  examination  of  more  than  700  additional 
cases  not  here  recorded. 


368  GENERAL  HEMATOLOGY. 

blasts  apparently  do  not  occur,  although  there  is  no  reason  why 
they  should  not,  if  the  anemia  happens  to  be  of  a  type  of  sufficient 
severity  to  provoke  marrow  changes. 

In  simple  appendicular  inflammation  uncom- 
Leucocytes.  plicated  by  pus,  gangrene,  or  peritonitis  there  is, 
as  a  rule,  little  or  no  increase  in  the  number  of 
leucocytes,  although  in  an  exceptional  case  the  leucocytosis  is 
fairly  well  defined.  Thus,  of  the  45  cases  of  this  form  of  the  disease 
below  referred  to,  less  than  9  per  cent,  were  accompanied  by  a 
count  in  excess  of  15,000,  the  maximum  estimate  being  17,100,  and 
the  average  8987  per  c.mm.  A  relatively  high  count  in  this 
variety  of  appendicitis  may  usually  be  attributed  to  a  limited 
periappendicular  peritonitis.  In  some  instances  it  is  possible  that 
the  increase  may  be  due  to  blood  inspissation  from  vomiting  and 
purging,  or  that  it  may  simply  represent  a  blood  finding  of  the 
associated  anemia. 

In  cases  with  abscess,  gangrene,  or  general  peritonitis  a  well- 
marked  leucocytosis  is  the  general  rule.  Few  cases  of  appen- 
dicular abscess  fail  to  increase  the  leucocyte  count  to  at  least 
15,000  or  20,000  to  the  c.mm.,  although  it  is  to  be  remembered 
that  should  the  purulent  focus  happen  to  be  so  effectually  walled 
off  that  absorption  of  toxic  material  is  practically  prevented,  so 
decided  an  increase  does  not  develop.  A  trivial  increase,  or, 
indeed,  an  absence  of  leucocytosis,  is  also  met  with  in  an  occa- 
sional grave  case  (such,  for  instance,  as  one  complicated  by  a 
general  purulent  peritonitis),  owing  to  the  prostration  of  the 
patient  from  the  systemic  poison  of  the  infection.  As  shown 
below,  the  average  count  in  purulent  and  gangrenous  appendicitis 
is  higher  than  the  maximum  count  in  the  catarrhal  form  of  the 
affection. 

A  high  leucocytosis  suggests  either  a  localized  abscess  or  a 
general  peritonitis,  for  the  differentiation  of  which  other  clinical 
data  are  absolutely  essential.  The  belief  is  current  that  if  a 
marked  leucocytosis  occurs  early  in  the  attack,  peritonitis  is  prob- 
able, and  if  it  occurs  after  the  first  week,  a  local  accumulation  of  pus 
is  suggested.  While  this  is  undoubtedly  true  in  many  instances, 
in  many  others  the  condition  of  the  appendicular  lesion  may  be 
wrongly  interpreted  if  too  great  reliance  is  placed  on  the  behavior 
of  the  leucocytes  in  connection  with  the  period  of  the  attack. 

Increase  in  the  purulent  focus  and  extension  of  peritonitis  are 
betrayed  by  an  increase  in  the  leucocyte  count,  provided  that  the 
patient's  powers  of  reaction  are  not  too  greatly  crippled.  In 
operative  cases  thorough  evacuation  of  the  abscess  is  followed 
within  a  few  days  by  a  decline  to  normal  in  the  number  of  leuco- 


APPENDICITIS. 


cytes.  Persistence  of  the  leticocytosis  after  the  third  or  fourth 
day  following  the  operation  may  usually  be  attributed  to  und rained 
pus  pockets  or  to  a  general  peritonitis. 

In  non-operative  cases  with  abscess  the  leucocytosis,  which 
becomes  well  developed  by  the  fourth  or  fifth  day  of  the  attack, 
persists  but  does  not  tend  to  increase  if  the  lesion  remains  local- 
ized; it  gradually  decreases  as  the  pus  collection  disappears; 
and  it  suddenly  increases  if  the  process  extends. 

To  sum  up,  absence  of  or  slight  leucocytosis  suggests  (a) 
simple  catarrhal  appendicitis;  (b)  fulminant  appendicitis;  or  (c) 
a  localized  pus  focus  from  which  no  absorption  occurs.  Well- 
marked  leucocytosis  indicates  (a)  a  local  abscess  from  which 
absorption  of  toxins  occurs;  (b)  general  peritonitis;  or  (c)  gangrene. 

The  following  table  shows  the  range  of  the  leucocytes  in  the 
German  Hospital  cases  to  which  reference  has  been  made : 

Number  of  Cases. 

Leucocytes  per  c.mm.  Non-purulent.    Purulent,  Perforative,  and 

Gangrenous. 

Above  50,000                                 o  1 

From  40,000-50,000                        o  o 

"     35,000-40,000                        o  2 

"     30,000-35,000                        o  o 

"     25,000—30,000                       o  6 

"     20,000-25,000                        o  16 

"     15,000-20,000                        4  38 

"     10,000-15,000                       10  24 

"      5,000-10,000                     25  7 

Below  5000                                   6  o 

Highest  1.7,100  per  c.mm.  58,500  per  c.mm. 

Lowest                                i,6oo    "      "  6,000  " 

Average                              8,987    "     "  17,955   "  " 

The  qualitative  changes  found  in  high  leucocyte  counts  are 
those  typical  of  an  ordinary  polynuclear  neutrophile  leucocytosis 
—a  large  absolute  and  relative  gain  in  polynuclear  forms  at  the 
expense  of  the  hyaline  mononuclear  cells. 

Findings  essentially  like  the  above  have  been  reported  by 
Cabot,1  Richardson,2  Bloodgood,3  and  Joy  and  Wright,4  in  America; 
by  Longridge,5  Gulland,6  and  French,7  in  Great  Britain;  by 

1  hoc.  cit.  2  Amer.  Jour.  Med.  Sci.,  1899,  vol.  cxviii,  p.  635. 

3  Prog.  Med.,  1901,  vol.  iv,  p.  216.  4  Med.  News,  1902,  vol.  lxxx,  p.  628. 

5  Brit.  Med.  Jour.,  1902,  vol.  ii,  p.  151 1;  also  Lancet,  1902,  vol.  ii,  p.  74. 

6  Scottish  Med.  and  Surg.  Jour.,  1903,  vol.  xii,  p.  157. 

7  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  1136. 

24 


37o 


GENERAL  HEMATOLOGY. 


Curschmann,1  Wassermann,2  Diitzmann,3  Federmann,4  Gern- 
gross,5  Coste,0  Kiihn,7  and  Stadler,*  in  Germany;  and  by  Cazin 
and  Gros,9  in  France. 

The  detection  of  iodophilia  is  a  great  diagnostic  aid.  Like 
leucocytosis,  it  measures  the  intensity  of  the  toxemia,  but  it  also 
develops  in  greatly  anemic  patients,  irrespective  of  their  systemic 
reaction  to  an  appendicular  lesion.  Iodophilia  is  most  marked 
in  cases  with  abscess,  gangrene,  and  local  or  general  peritonitis ; 
in  pus  cases  the  reaction  persists  so  long  as  the  pus  remains 
pent  up,  but  it  rapidly  disappears  after  adequate  drainage  is 
established — usually,  in  the  author's  cases,  within  thirty-six  hours 
or  so.  Thus  it  appears  that  the  iodin  reaction  has  much  the 
same  meaning  as  leucocytosis,  but  it  is  even  a  more  sensitive  sign 
than  the  latter,  since  it  frequently  betrays  a  sepsis  too  slight  to 
excite,  or  so  grave  as  to  stifle,  a  leucocyte  increase.  Locke,10 
from  a  study  of  61  cases  of  appendicitis,  lays  stress  on  iodophilia 
as  a  negative  sign;  rarely,  if  ever,  does  it  fail  to  develop  when 
sepsis  is  present. 

The  conditions  which  may  more  or  less 
Diagnosis,  closely  simulate  an  acute  attack  of  appendicitis 
are  numerous,  and  unfortunately  it  happens  that 
just  those  lesions  in  which  the  resemblance  is  closest  often  produce 
blood  changes  identical  with  those  of  appendicitis.  Thus,  leuco- 
cytosis is  the  rule  in  pyosalpinx,  ovarian  abscess,  ectopic  pregnancy, 
pyonephrosis,  perinephritic  abscess,  hepatic  abscess,  empyema  of  the 
gall-bladder,  mesenteric  thrombosis,  and  malignant  disease  of  the 
cecum,  all  of  which  may  be  confused  with  an  appendicular  abscess. 
Iodophilia  also  occurs  in  these  conditions,  save  perhaps  in  ectopic 
gestation. 

Such  a  large  proportion  of  cases  of  hepatic  and  renal  colic  are 
accompanied  with  acute  inflammatory  complications,  giving  rise 
to  leucocytosis,  that  these  conditions  cannot  be  differentiated 
with  any  degree  of  confidence  from  appendicitis  simply  by  an 
examination  of  the  blood.  The  same  is  true  of  dysmenorrhea, 
in  which  inflammatory  changes  in  the  uterus  may  constitute  the 
factor  of  a  leucocyte  increase.  Acute  gastritis  is  sometimes  ac- 
companied by  a  well-marked  leucocytosis,  and  sometimes  by 

1  Munch,  med.  Wochenschr.,  1901,  vol.  xlviii,  pp.  1907  and  1962. 

2  Arch.  f.  klin.  Chir.,  1903,  vol.  lxix,  p.  392. 

3  Sem.  med.,  1903,  vol.  xxiii,  p.  324. 

4  XXII.  Cong.  f.  Chir.,  Berlin,  1903;  also  Sem.  med.,  1904,  vol.  xxiv,  p.  206. 

5  Munch,  med.  Wochenschr.,  1903,  vol.  1,  p.  1586. 

6  Ibid.,  1902,  vol.  xlix,  p.  2038.         7  Ibid.,  1902,  vol.  xlix,  pp.  2033  and  2085. 

8  Jour.  Amer.  Med.  Assoc.,  1903,  vol.  xli,  p.  216. 

9  Sem.  med.,  1903,  vol.  xxiii,  p.  141. 

10  Boston  Med.  and  Surg.  Jour.,  1902,  vol.  cxlvii,  p.  289. 


ARTHRITIS    1)10  FOR  MANS. 


371 


none  at  all,  so  that  the  blood  count  cannot  be  relied  upon  as  a 
clue  in  distinguishing  this  disease  from  appendicitis. 

Simple  enteralgia,  gastralgia,  and  ovarian  neuralgia  may  be 
ruled  out  if  a  leucocyte  increase  is  present,  as  also  may  be  intestinal 
obstruction,  provided  that  the  latter  is  not  complicated  by  inflam- 
matory changes,  by  gangrene,  or  by  malignant  disease.  In 
lead  colic  there  is  often  a  pronounced  leucocytosis,  especially  in 
patients  with  acutely  toxic  symptoms;  but  granular  basophilia  of 
the  erythrocytes  can  be  detected  even  in  the  earliest  stages  of 
plumbism,  while  in  appendicitis  this  change  is  found  only  in 
highly  anemic  subjects. 

The  presence  of  a  leucocytosis  is  sufficient  to  exclude  a  non- 
inflammatory ovarian  cyst  and  a  movable  kidney,  and  the  same 
sign  is  of  no  little  value  in  ruling  out  enteric  fever  if  no  leuco- 
cyte-raising complications  are  apparent. 

The  simple  fact  of  the  presence  or  absence  of  a  leucocytosis  is 
more  often  misleading  than  useful  in  the  diagnosis  of  appendicitis, 
for  this  sign,  to  be  of  any  real  value,  must  invariably  be  corre- 
lated with  other  more  clinical  manifestations.  Appendicitis 
should  never  be  ruled  out  because  leucocytosis  is  absent,  nor 
should  a  moderate  leucocyte  count  be  considered  an  indication 
of  the  benignancy  of  the  lesion.  A  count  in  excess  of  20,000, 
particularly  if  it  persists  or  increases,  may  be  relied  upon  as  a 
certain  sign  of  pus  or  its  consequences,  and  is  sufficient  to 
warrant  operative  interference  if  the  symptoms  point  to  the 
appendix  as  the  seat  of  the  trouble.  Counts  of  less  than 
20,000  cannot  be  depended  upon  to  reflect  the  character  of  the 
local  lesion,  since  an  increase  to  practically  this  figure  may  be 
found  occasionally  in  mild  catarrhal  cases,  as  well  as  in  those  with 
purulent  foci.  In  the  writer's  experience  the  behavior  of  the 
leucocytes  throws  a  much  clearer  light  upon  the  progress  of  the 
disease  in  both  operative  and  non-operative  cases  than  it  does 
upon  the  initial  diagnosis,  which  should  be  determined  chiefly  by 
other  clinical  methods. 

The  absence  of  iodophilia  is  a  dependable  sign  that  no  active 
inflammation  of  the  appendix  exists,  although  its  presence  does 
not  necessarily  mean  appendicitis,  as  remarked  above. 


VIII.  ARTHRITIS  DEFORMANS. 

In  spite  of  their  pallor,  sufferers  from  arthritis  deformans 
seldom  have  decided  anemia.  Recent  hematological  work  in  this 
disease  shows  that  most  cases  have  normal  hemoglobin  and  erythro- 


372 


c ;  1  :n  k ral  hematology. 


cyte  values,  and  that  anemia,  when  it  does  develop,  is  generally 
moderate  and  traceable  to  causes  other  than  the  joint  lesions. 
McCrae's  report1  shows  an  average  hemoglobin  percentage  of  70.6 
in  33  cases,  and  an  average  erythrocyte  count  of  4,468,000  per 
c.mm.  in  29.  Erving's  counts 2  in  40  cases  show  an  average 
hemoglobin  percentage  of  94,  with  a  range  between  80  and  100, 
and  an  erythrocyte  count  averaging  5,112,000,  with  a  range 
between  4,148,000  and  5,980,000.  These  figures  evidence  a  much 
less  marked  anemia  than  that  detailed  by  earlier  writers,  for  ex- 
ample by  Bannatyne,3  who  found  that  the  hemoglobin  commonly 
ranged  between  40  and  80  per  cent.,  and  the  erythrocytes  between 
3,000,000  and  4,000,000.  Histological  changes  in  the  erythrocytes 
are  conspicuous  by  their  absence. 

Leucocytosis  rarely  accompanies  arthritis  deformans,  and  When 
present,  can  generally  be  referred  to  some  complicating  lesion. 
Of  McCrae's  33  cases,  but  9  showed  definite  leucocytosis,  the 
average  count  being  7600;  in  Erving's  40  cases  the  leucocytes 
exceeded  10,000  per  c.mm.  in  but  5  instances,  and  averaged  8885. 
Differential  changes  are  trifling  and  do  not  occur  in  all  cases. 
They  consist  in  nothing  more  than  a  moderate  diminution  in  the 
polynuclear  neutrophiles  with  a  proportionate  lymphocyte  in- 
crease. 

IX.  ASIATIC  CHOLERA. 

In  many  cases  there  is  great  difficulty  in 
General     obtaining  a  sufficient  quantity  of  blood  for  clin- 
Features.    ical  examination,  even  from  a  deep  puncture. 

This  peculiarity,  which  has  been  attributed  to 
excessive  dryness  of  the  tissues  from  drains  upon  the  body  fluids, 
is  most  pronounced  in  the  algid  stage  of  the  disease. 

The  great  decrease  in  the  alkalinity  of  the  blood  in  Asiatic 
cholera,  sometimes  spoken  of  as  an  acid  reaction,  was  first  de- 
termined by  C.  A.  Schmidt4  by  a  series  of  elaborate  analyses 
made  in  1850,  since  which  time  similar  findings  have  been  noted 
by  Cantani,5  Straus,6  and  others. 

The  density  of  the  blood  mass  is  found  to  be  increased,  es- 
pecially in  those  cases  in  which  the  blood  is  highly  inspissated; 
in  such  instances  the  specific  gravity  may  rise  to  as  high  as  1.073. 
The  agglutination  of  cholera  vibrios  by  the  blood  serum  of 

1  Jour.  Amer.  Med.  Assoc.,  1904,  vol.  xlii,  p.  1. 

2  Amer.  Med.,  1903,  vol.  vi,  p.  440.  3  Lancet,  1896,  vol.  ii,  p.  1510. 

4  "  Charakteristik  der  epidemischen  Cholera  gegeniiber  verwandten  Transsuda- 
tionsanomilien,"  Leipsic,  1850. 

5  Centralbl.  f.  d.  med.  Wissenschaft,  1894,  vol.  xxii,  p.  7S5. 

6  Compt.  rend.  Soc.  biol.,  Paris.  1883,  vol.  iv,  p.  569. 


ASIATIC:  CHOLKRA. 


373 


cholera  patients  was  first  applied  as  a  clinical  lest  by  Achard 
and  Bensaude,1  these  investigators  finding  that  the  reaction  may 
occur  as  early  as  the  reputed  first  day  of  the  illness  and  as  late 
as  the  fourth  week  after  recovery.  Clinically,  the  test  may  be 
made  either  with  dried  blood  or  with  serum. 

The  studies  of  Biernacki 2  and  of  Okladnych,3 
Hemoglobin  which  together  include  the  investigation  of  62 
and         cases,   furnish   the   most   complete   data  con- 
Erythrocytes.  cerning  the  changes  affecting  these  elements. 

Both  of  these  observers  found  a  more  or  less 
marked  polycythemia  with  a  proportionate  increase  in  the  hemo- 
globin percentage,  the  erythrocyte  count  in  many  cases  being 
between  6,500,000  and  7,500,000,  and  in  one  case  reaching  a 
maximum  of  8,000,000.  The  increase  may  often  be  observed 
within  a  few  hours  after  the  onset  of  the  infection.  Concentra- 
tion of  the  blood  is  to  be  considered  as  the  cause  of  these  high 
counts,  which  are,  as  a  rule,  highest  in  cases  characterized  by 
pronounced  emesis  and  purging.  No  constant  relation  between 
the  degree  of  polycythemia  and  the  gravity  of  the  infection  can 
be  distinguished. 

The  above- quoted  authors  found  high-grade 
Leucocytes,  leucocytosis  to  be  the  almost  invariable  rule, 
the  increase  in  leucocytes  being  not  parallel 
with,  but  rather  relatively  greater  than,  the  accompanying  in- 
crease in  erythrocytes.  It  occurs  both  in  mild  and  in  severe 
cases,  as  early  as  within  twelve  hours  after  the  onset  of  the  dis- 
ease, and  as  late  as  the  third,  fourth,  or  sixth  day.  It  may  be 
present  both  in  the  algid  stage  and  in  the  stage  of  reaction,  but  is 
likely  to  be  more  decided  in  the  former.  The  degree  of  leucocy- 
tosis may  range  from  a  minimum  count  of  14,000  to  a  maximum 
of  60,000  cells  per  c.mm.,  the  case  of  average  severity  showing 
an  increase  to  about  25,000  or  30,000.  Preagonal  leucocytosis 
may  be  pronounced,  counts  of  50,000  being  not  uncommon. 
Biernacki  states  that  "all  cases  which  in  the  algid  stage  show 
a  leucocytosis  of  40,000  to  60,000  soon  prove  fatal."  On  the 
contrary,  an  absence  of  leucocytosis  cannot  be  regarded ^  as  a 
surety  that  the  patient  will  recover.  In  a  trivial  infection  distinct 
leucopenia  has  been  observed,  but  this  is  rare.  Rogers,4  who  in- 
variably found  leucocytosis  in  23  cases,  also  believes  that  the 
higher  the  count,  the  worse  the  prognosis.  Of  9  of  his  patients 
with  counts  of  less  than  20,000,  4  died;  of  14  with  counts  ranging 


1  Presse  med.,  1896,  vol.  xvi,  p.  504. 

2  Deutsch.  med.  Wochenschr.,  1895,  vol.  xxi,  p.  795. 

3  Cited  by  Biernacki,  loc.  cit.  .  4  Lancet,  1902  vol.  ii,  p.  659. 


374 


GKNKRAL  II  KM ATOLOGY. 


between  20,000  and  46,000,  11  died.  Concentration  of  the  blood 
does  not  altogether  account  for  the  leukocytosis  of  cholera,  for 
the  influence  of  the  specific  infection  as  a  factor  is  thought  to  be 
most  active. 

The  leucocytosis  involves  chiefly  the  polynuclear  neutrophiles, 
but  not  so  conspicuously  as  in  most  other  infections,  since  the  per- 
centage of  these  cells  in  cholera  seldom  exceeds  80.  Rogers  first 
described  this  peculiarity,  and  also  drew  attention  to  the  behavior 
of  the  lymphocytes.  The  small  lymphocytes,  he  found,  are 
usually  outnumbered  to  the  extent  of  two  to  one  by  the  large 
mononuclear  forms,  the  latter's  increase  becoming  more  marked 
as  the  disease  progresses,  and  being  especially  so  in  fatal  cases. 
He  finds  that  an  excessive  increase  in  this  form  of  cell  is  of  bad 
prognosis:  of  18  cases  with  counts  exceeding  2000  large  lym- 
phocytes per  c.mm.,  14  died;  while  of  5  in  which  these  cells  num- 
bered less  than  2000  but  a  single  patient  died.  The  eosinophiles 
rarely  numbered  more  than  a  fraction  of  one  per  cent.  Sherring- 
ton 1  has  found  the  mast  cells  notably  increased  in  some  instances. 

Leucocytosis  is  more  constant  and  tends  to 
Diagnosis,  reach  a  higher  degree  in  Asiatic  cholera  than  in 
any  other  non-choleraic  disease  with  similar 
symptoms.  In  acute  dysentery  and  in  ptomain  poisoning,  however, 
the  counts  may  be  identical  with  those  of  cholera,  but  the  character- 
istic lymphocyte  formula  of  the  latter  is  wanting.  From  the 
viewpoint  of  prognosis  this  differential  change  and  the  height  of 
the  total  leucocyte  count  are  obviously  helpful  signs. 


X.  ASTHMA  AND  EMPHYSEMA. 

In  long-standing  cases  moderate  secondary  anemia  involving 
chiefly  a  hemoglobin  loss  may  be  found,  for  in  many  instances 
the  general  debility  of  the  patient  or  the  presence  of  lesions  of 
other  organs  is  quite  adequate  to  give  rise  to  such  a  change. 
In  cyanotic  patients  the  anemia  may  be  hidden  by  the  polycy- 
themia arising  from  circulatory  disturbances,  this  deceptive  blood 
concentration  being  most  conspicuous  during  an  asthmatic  par- 
oxysm. 

Little  or  no  increase  above  the  normal  standard  in  the  number 
of  leucocytes  is  the  usual  condition,  although  these  cells  may  show 
a  considerable  increase  in  cases  associated  with  acute  bronchitis, 
and  also  during  an  asthmatic  attack.    Gabritschewsky,2  Fink,3  von 

1  Proc.  of  the  Roy.  Soc,  London,  1894,  vol.  lv,  p.  189. 

2  Arch.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  xxviii,  p.  83- 

3  Inaug.  Diss.,  Bonn,  1890. 


BRONCHITIS. 


375 


Noorden,1  Billings,2  and  others  have  called  attention  to  the  pres- 
ence of  an  eosinophil  increase  in  both  asthma  and  emphysema. 
From  10  to  20  per  cent,  of  this  type  of  cells  is  not  an  unusual 
proportion,  both  in  cases  with  and  in  those  without  leucocytosis, 
while  in  one  case  Billings  has  reported  three  consecutive  counts 
of  33.9,  38.2,  and  53.6  per  cent,  respectively,  with  correspond- 
ing total  leucocyte  estimates  of  7600,  7500,  and  8300  per  c.mm. 
In  true  bronchial  asthma  the  eosinophile  increase  develops  shortly 
before  the  paroxysm,  and  persists  during  and  for  a  short  time  after 
it,  disappearing  in  the  interval  between  the  seizures.  This  sign 
is  regarded  of  value  in  differentiating  true  bronchial  asthma  from 
the  dyspnea  due  to  renal  and  cardiac  lesions,  since  in  the  latter 
the  eosinophils  are  never  increased,  and  it  is  also  considered 
of  some  clinical  utility  in  heralding  an  impending  asthmatic 
paroxysm. 

XI.  BRONCHITIS. 

With  the  exception  of  a  slight  oligochromemia,  which  is  fre- 
quently present  in  severe  cases  with  high  temperatures,  the 
erythrocytes  and  their  hemoglobin  content  remain  practically 
normal  in  all  forms  of  bronchial  inflammation. 

Acute  catarrhal  bronchitis  of  the  larger  tubes  is  ordinarily  un- 
attended by  leucocytosis,  but,  unfortunately  for  diagnostic  pur- 
poses, an  occasional  case  shows  a  marked  increase.  Thus,  in  four 
of  Cabot's  seventeen  cases3  the  counts  were  17,600,  23,500,  26,000, 
and  41,000  respectively,  while  in  eleven  the  leucocytes  numbered 
more  than  10,000  per  c.mm.  In  chronic  bronchitis  leucocytosis 
rarely  if  ever  occurs.  Extension  of  the  inflammation  to  the  finer 
tubules  and  vesicular  structure  causes  a  leucocytosis  identical 
with  that  of  croupous  pneumonia  (q.  v.). 

Inflammation  of  the  tracheobronchial  glands,  according  to 
Carriere,4  sets  up  a  decided  mononucleosis.  Lichtwitz  and 
Sabrazes 5  found  this  change  in  the  blood  of  children  with  naso- 
pharyngeal adenoids,  the  mononuclear  increase  in  such  cases  dis- 
appearing after  removal  of  the  growths. 

1  Zeitschr.  f.  klin.  Med.,  1892,  vol.  xx,  p.  98. 

2  N.  Y.  Med.  Jour.,  1897,  vol.  lxv,  p.  691. 

3  hoc.  cit.  4  Sem.  med.,  1902,  vol.  xxii,  p.  44. 
5  Arch,  de  med.  des  Enf.,  1901,  vol.  iv,  p.  120. 


o  / 


6  GENERAL  HEMATOLOGY. 


XII.  BUBONIC  PLAGUE. 

Slow,  imperfect  coagulation  of  the  blood  has 
General     been  found,  and,  in  virulent  cases,  absolute  non- 
Features.     coagulability.    This   was  noted  by  Alice  M. 

Corthorn  1  in  10  of  12  fatal  cases  of  pest,  whose 
blood,  kept  sealed  in  Wright's  tubes  for  three  weeks  and  longer, 
showed  no  sign  of  clot  formation,  but  resembled  simply  a  dark- 
red,  treacle-like  fluid.  Jennings  2  found  that  rouleaux  formation 
is  but  feebly  exhibited. 

Since  1894,  when  Kitasato  and  Yersin,  working  independently, 
simultaneously  discovered  the  Bacillus  pestis  bubonicce  in  the 
circulating  blood  of  patients  infected  with  plague,  this  organism 
has  been  repeatedly  isolated  from  the  blood  by  many  different  ob- 
servers. In  a  careful  bacteriological  study  of  27  cases  Ogata  g 
also  frequently  found  in  the  blood,  especially  in  severe  infections, 
a  micro-organism  morphologically  similar  to  Frankel's  pneu- 
mococcus,  the  significance  of  this  unidentified  organism  being 
undetermined.  The  same  observer  calls  attention  to  the  fact  that 
blood  from  patients  convalescent  from  nineteen  to  sixty-five  days, 
although  giving  negative  results  by  cultural  methods,  when  in- 
jected into  mice  proves  rapidly  fatal  to  these  animals,  in  whose 
tissues  the  plague  bacillus  may  be  recovered  in  pure  culture.  The 
relatively  large  number  of  positive  results  to  be  obtained  from 
bacteriological  blood  examinations  in  this  disease,  especially  in  its 
septicemic  form,  attaches  to  the  procedure  no  small  diagnostic 
value.  The  German  Plague  Commission's  results4 — 43  positive 
findings  in  a  series  of  124  cases  examined — are  probably  represen- 
tative of  the  value  of  blood  culturing  in  this  infection.  Powell's 
studies0  show  but  15  positive  cultures  in  117  cases.  Cultural 
methods  with  blood  drawn  directly  from  a  vein  give,  of  course, 
the  most  favorable  results,  but  the  bacilli  may  be  often  detected 
in  the  stained  cover-glass  specimen  of  finger  blood,  in  which  they 
appear  as  short  rods,  tending  to  group  together  in  chains  or  in 
pairs,  exhibiting  bipolar  staining  and  decolorizing  by  Gram's 
method.  In  view  of  the  fact  that  the  peripheral  blood  contains 
but  small  numbers  of  the  bacilli,  Rees 6  advises  making  large 
films  on  slides  rather  than  cover-glass  specimens,  should  direct 
examination  of  the  stained  film  be  attempted. 

1  Brit.  Med.  Jour.,  1902,  vol.  i,  p.  1143.    '  2  "Manual  of  Plague,"  London,  1903. 

3  Centralbl.  f.  Bakt.  u.  Parasit,  1897,  vol.  xxi,  p.  769. 

4  Cited  by  Novy,  Amer.  Jour.  Med.  Sci.,  1901,  vol.  exxii,  p.  416. 

5  Indian  Med.  Gaz.,  1904,  vol.  xxxix,  p.  41. 
c  Brit.  Med  Jour.,  1900,  vol.  ii,  p.  1236. 


BUBONIC  PLAGUE. 


377 


The  agglutination  of  the  plague  bacillus  by  the  blood  serum 
from  plague  subjects  has  been  noted  by  a  number  of  different 
investigators,  but  thus  far  no  clinical  application  of  the  reaction 
has  been  made.  The  inconstancy  with  which  the  reaction  occurs— 
for  it  may  frequently  be  absent 'in  both  the  mildest  and  the  most 
severe  cases —  and  the  variable  degrees  of  serum  dilution  neces- 
sary for  its  production  appear  to  bar  the  acceptance  of  the  test  as 
a  reliable  diagnostic  sign.  The  British  Indian  Plague  Commis- 
sion 1  concludes  that  "no  practical  value  attaches  to  the  method  of 
serum  diagnosis  in  the  case  of  plague." 

The  striking  bactericidal  action  of  plague  serum  upon  the  Bacil- 
lus pestis  has  been  taken  by  Row 2  as  the  basis  of  a  clinical  test.  A 
drop  of  blood  serum  from  a  plague  patient  is  mixed  with  a  loopful 
of  a  saline  emulsion  of  the  Bacillus  pestis,  and  from  this  mixture 
a  hanging-drop  culture  is  made  and  placed  in  the  dark  for  twenty- 
four  hours  at  laboratory  temperature.  The  cover-glass  is  then 
fixed,  stained  with  thionin,  and  examined  microscopically.  If  the 
serum  used  in  the  test  is  from  a  person  infected  with  plague^  the 
twenty-four-hour-old  culture  shows  either  no  growth  of  the  bacillus 
or,  at  the  most,  a  very  few  distorted  and  atypical  organisms.  In 
control  cases,  with  normal  serum,  the  growth  is  abundant.  Row 
considers  this  test  of  real  value  in  estimating  the  protective  effects 
of  Haffkinization.  Its  usefulness  as  a  clinical  means  of  diagnosing 
plague  is  restricted  by  the  time  required  (twenty-four  hours)  for 
the  completion  of  the  reaction,  though  in  suspected  cases  with 
poorly  developed  symptoms  the  test  may  prove  of  value. 

According  to  Aoyoma's  studies,3  the  hemo- 

Hemoglobin  .  globin  and  the  erythrocytes  are  both  decidedly 
and  increased  above  normal  in  the  majority  of  cases. 
Erythrocytes.  Of  the  six  cases  examined  by  this  writer,  five 
showed  marked  polycythemia,  the  highest  count 
being  8,190,000,  and  the  average  6,976,666.  Septic  cases  may 
develop  secondary  anemia  of  variable  intensity.  Qualitative 
changes  in  the  erythrocytes,  it  is  to  be  presumed,  are  not  con- 
spicuous, since  no  mention  of  such  alterations  is  made. 

In  two- thirds  of  the  cases  just  quoted  marked 

Leucocytes,  increase  in  the  number  of  leucocytes  was  found, 
the  gain  being  greater  than  is  ordinarily  met  with 
in  any  condition  except  leukemia;  the  count  exceeded  100,000 
in  four  instances,  and  averaged  for  the  six  96,666.    In  fulminant 

1  Brit.  Med.  Jour.,  1903,  vol.  i,  pp.  1093,  1155,  1220,  1279. 

2  Ibid.,  1902,  vol.  ii,  p.  1895.  .      .  . 

3  Mittheilungen  aus  d.  Med.  Fac.  d.  Kaiserlich-Japanischen  Umversitat,  lokio, 

1895,  vol.  iii,  p.  115. 


378 


( i  E  N  ERAL  HEMATOLOGY. 


types  of  plague  extreme  leucopenia,  due  to  the  overpowering 
toxemia,  is  not  unusual,  and  in  very  mild  cases  the  number  of 
leucocytes  may  be  normal.  The  increase  was  due  usually  to  a 
disproportionately  large  percentage  of  polynuclear  neutrophiles, 
but  in  some  cases  "large  and  small  mononuclear  white  cells" 
were  observed.  The  eosinophiles  were,  as  a  rule,  conspicuous 
by  their  absence.  Rogers,1  whose  leucocyte  counts  varied  from 
20,000  to  60,000,  also  observed  a  lymphocytosis,  and  emphasizes 
the  fact  that  in  most  cases  the  polynuclear  neutrophiles  show  little 
or  no  relative  increase.  Contrary  to  Aoyoma's  findings,  Zinno  2 
has  noted,  in  an  occasional  case,  a  great  abundance  of  eosinophiles 
of  the  myelocytic  type,  of  the  ordinary  polynuclear  variety,  and  of  a 
form  transitional  between  the  two;  in  one  of  his  cases  the  eosino- 
philic myelocytes  numbered  13  per  cent,  of  the  total  leucocyte 
count. 

The  blood  plaques  are  in  most  cases  notably  increased  in 
number. 

XIII.  BURNS. 

Rapidly  developing  and  marked  polycythemia,  equally  striking 
leucocytosis,  and  a  plaque  increase  are  the  features  of  clinical 
interest  in  the  blood  picture  of  the  severely  burned.  To  the  naked 
eye  the  blood  has  a  deep  purplish  color  and  flows  very  sluggishly. 

Locke's  studies3  of  ten  cases  of  severe  burns  show  that  within 
a  few  hours  after  the  accident  a  marked  increase  in  the  number 
of  erythrocytes  takes  place,  amounting  in  favorable  cases  to  be- 
tween 1,000,000  and  2,000,000  cells  to  the  c.mm.,  and  in  fatal  cases 
to  between  2,000,000  and  4,000,000.  This  polycythemia  may  be 
explained  chiefly  by  venous  stasis  and  partly  by  loss  of  the  blood 
plasma.  Structural  changes  in  the  erythrocytes  are  not  con- 
spicuous. The  leucocytes  rapidly  increase,  reaching  a  count  of 
from  30,000  to  40,000  per  c.mm.  in  non-fatal  burns,  and  of  50,000 
or  more  in  patients  who  die.  The  percentage  of  polynuclear 
neutrophiles  increases,  although  not  to  so  high  a  figure  as  is 
commonly  found  in  ordinary  inflammatory  leucocytosis.  De- 
generative changes,  especially  of  their  protoplasm,  involve  many 
of  these  cells,  as  well  as  the  other  granular  leucocytes,  and  are 
marked  in  parallelism  to  the  severity  of  the  lesion.  Myelocytes 
occur  in  small  numbers,  particularly  in  cases  having  a  high 
leucocytosis.  The  blood  plaques  are  greatly  increased  in  practi- 
cally every  instance. 

1  Lancet,  1902,  vol.  ii,  p.  660. 

2  Centralbl.  f.  allg.  Path.  u.  path.  Anat.,  1902,  vol.  xiii,  p.  410. 

3  Boston  Med.  and  Surg.  Jour.,  1902,  vol.  cxlvii,  p.  480. 


CHLOROMA. 


379 


XIV.  CHLOROMA. 
The  blood  changes  in  this  rare  disease  closely  resemble  those 
of  lymphatic  leukemia,  namely,  marked  anemia  with  absolute 
lymphocytosis.  The  hemoglobin  and  erythrocytes  progressively 
diminish  as  the  disease  runs  its  course,  and  eventually  may  sink 
quite  as  low  as  in  pernicious  anemia.  In  a  case  reported  by 
Dunlop  1  the  hemoglobin  fell  from  32  to  12  per  cent.,  and  the  ery- 
throcytes from  1,800,000  to  850,000  per  c.mm.  during  a  period  of 
but  four  weeks.  Estimates  not  dissimilar  from  these  have  been 
recorded  by  a  number  of  other  writers,  notably  by  Rosenblath 
and  Risel,2  by  Gumbel,3  and  by  Weinberger.4  Misshapen  and 
otherwise  degenerate  erythrocytes,  together  with  a  variable  number 
of  normoblasts,  make  their  appearance  as  the  anemia  increases 
in  degree. 

High  leucocyte  counts,  involving  absolute  lymphocytosis 
(small  celled),  are  the  rule  in  the  cases  thus  far  reported.  Ex- 
ceptionally there  is  simply  lymphocytosis  of  the  relative  form,  as  m 
a  case  reported  by  Bramwell5  with  95  per  cent,  of  lymphocytes  and 
a  leucocyte  count  of  8000.  Early  in  the  disease  the  total  count  is 
not  excessive, — 20,000  or  30,000, — but  after  a  few  weeks  it  may 
attain  much  higher  figures— 75,000  to  100,000  or  more.  Dunlop's 
case  at  one  time  showed  a  leucocyte  count  of  245,000  per  c.mm. 
Differentially,  the  count  in  chloroma  differs  but  slightly  from  that 
of  lymphatic  leukemia.  The  percentage  of  lymphocytes  is  rarely 
so  high  as  in  the  latter,  and  mast  cells  are  not  so  numerous,  but 
myelocytes  are  more  abundant.  Eosinophiles,  both  polynuclear 
and  myelocytic,  were  numerous  in  a  case  studied  by  Dock.6  These, 
however,  are  minor  differences,  and  do  not  serve  as  reliable 
criteria  of  differentiation. 

Chloroma  has  a  superficial  resemblance  to  exophthalmic 
goiter,  and  very  closely  counterfeits  acute  lymphatic  leukemia. 
Indeed,  one  is  strongly  tempted  to  agree  with  Dock  in  considering 
it  a  malignant  form  of  leukemia,  from  which  it  differs  chiefly  in 
being  more  violently  neoplastic  and  in  forming  greenish  infiltrations 
and  metastases.  Graves'  disease  is  readily  differentiated  by  the 
blood  picture.  The  clinical  differences  between  chloroma  and 
leukemia  are  dealt  with  under  the  latter  disease.    (See  p.  326.) 

1  Brit.  Med.  Jour.,  1902,  vol.  i,  p.  1072. 

2  Deutsch.  Arch.  f.  klin.  Med.,  1902,  vol.  lxxii,  p.  1. 

3  Virchow's  Arch.,  1903,  vol.  clxxi,  p.  504. 

4  Zeitschr.  f.  klin.  Med.,  1903,  vol.  1,  p.  383. 

5  Lancet,  1902,  vol.  i,  pp.  451  and  520.      6  Med.  News,  1904,  vol.  lxxxiv,  p.  955. 


3^0  GENERAL  HEMATOLOGY. 


XV.  CHOLELITHIASIS. 

In  impacted  calculi  with  jaundice,  coagulation 
General     is  frequently  but  not  invariably  delayed,  but  in 
Features,    gall-stone  complicated  by  phlegmonous  cholan- 
gitis or  other  purulent  sequelae,  hyperinosis  is 
observed,  and  coagulation  is  generally  more  rapid  than  normal. 
In  28  cases  of  cholelithiasis  the  writer  found  that  clotting  occurred 
in  less  than  five  minutes  in  7,  in  from  five  to  ten  minutes  in  16, 
and  in  longer  than  ten  minutes  in  5.    In  60  per  cent,  clotting  was 
delayed,  the  coagulation  time  for  these  cases  averaging  eight  and 
one-half  minutes.    The  general  effects  of  bile  upon  the  blood, 
elsewhere  noted,  may  also  be  detected  when  marked  jaundice 
develops.    (See  "Cholemia"  and  "Icterus.") 

Positive  results  from  bacteriological  examination  of  the  blood 
have  frequently  been  obtained  in  cholelithiasis,  streptococci  having 
been  isolated  by  Netter,1  staphylococci  and  colon  bacilli  by  Sitt- 
manV  streptococci  and  pneumococci  by  Canon,3  and  various 
bacteria  of  unknown  identity  by  other  investigators. 

Hemoglobin            Number  of       Erythrocytes                 Number  of 
Percentage.                Cases.             per  c.mm.  Cases. 
From  90-100  12       Above  5, 000,000  13 

ex      0  ^ 

9°  23       From  4,000,000-5,000,000  .58 

70-80  A7  u 

«     60-70  20  3.000,000-4,000,000  .34 

"     50-60   8  "     2,000,000-3,000,000  .10 

"     40-50   5  "     1,000,000-2,000,000  .  1 

"      3°-4°   I 

"      20-30   3 

Below  20   1 

Average,     73.5  per  cent.  Average,  4,o8o,ii7perc.mm. 

Maximum,  98.0       "  Maximum,  5,390,000  "  " 

Minimum,  15.0       "  Minimum,  1,040,000  "  " 

Moderate  oligochromemia  is  found  in  the 
Hemoglobin    greater  proportion  of  cases,  but  a  decided  loss 
and         either  of  hemoglobin  or  of  erythrocytes  is  com- 
Erythrocytes.  paratively  rare.    In  general  terms  it  may  be 
conservatively  stated  that  the  hemoglobin  loss 
on  the  average  amounts  to  about  30  per  cent.,  and  that  the  cel- 

1  Progres  med.,  1886,  vol.  xiv,  p.  992. 

2  Deutsch.  Arch.  f.  klin.  Med.,  1894,  vol.  liii,  p.  323. 

3  Deutsch.  med.  Wochenschr.,  1893,  vol.  xix,  p.  103S. 


CYANOTIC  POLYCYTHEMIA. 


lular  decrease  approximates  15  per  cent,  of  the  normal  standard. 
In  occasional  instances,  notably  those  in  which  suppuration  or 
sepsis  coexists,  the  anemia  is  of  a  more  intense  grade,  and  may 
be  associated  with  various  changes  indicative  of  cellular  degen- 
eration. In  116  cases  of  cholelithiasis  the  foregoing  estimates  of 
the  hemoglobin  and  erythrocytes  were  obtained  at  the  initial 
examinations. 

Simple  gall-stone  does  not  of  itself  excite  the 
Leucocytes,  slightest  increase  in  the  number  of  leucocytes, 
but  nevertheless  leucocytosis,  typically  _  polynu- 
clear  in  type,  is  a  rather  common  feature  of  the  blood  picture  in 
this  disease,  owing  to  the  fact  that  such  a  large  percentage  of 
cases  is  complicated  by  acute  inflammatory  changes.  Thirty-three 
of  the  116  cases  just  mentioned  had  a  count  of  more  than  10,000 
cells  to  the  c.mm.  The  following  resume  of  the  examinations 
illustrates  the  range  of  leucocytes  in  the  series: 

Leucocytes 
Per  c.mm. 

From  20,000-30,000  

"     15,000-20,000  ■ 

"  10,000-15,000  

"  5,000-10,000  

Below  5,000  

Average,      9,623  per  c.mm. 
Maximum,  26,000    "  " 
Minimum,    4,500    "  " 

The  presence  of  a  leucocytosis  excludes  simple 
Diagnosis,    biliary  colic,  and  indicates  as  the  cause  of  the  in- 
crease some  other  lesion,  such,  for  example^  as 
phlegmonous  cholangitis  or  cholecystitis,  hepatic  abscess,  peritonitis, 
or  malignant  disease.    Hepatic  and  renal  colics  cannot  be  differ- 
entiated by  the  blood  count. 

The  surgeon  should  remember  that  cases  with  delayed  coagu- 
lation may  bleed  freely,  even  fatally,  when  the  knife  is  used,  and 
that  to  such  patients  remedies  which  promote  clotting  should  be 
given  before  operating. 

XVI.  CYANOTIC  POLYCYTHEMIA. 

In  this  new  clinical  entity,  first  described  by  Saunby  and  Rus- 
sell,1 the  hemoglobin  and  erythrocyte  values  attain  extraordinarily 

1  Lancet,  1902,  vol.  i,  p.  515. 


Number  of 
Cases. 

...  6 
...  8 

...19 

---74 
...  9 


3^2 


GENERAL  HEMATOLOGY. 


high  figures.  Osier,1  who  has  studied  the  condition  in  detail, 
reports  one  ease  with  a  hemoglobin  percentage  of  165  and  an 
erythrocyte  count  of  10,200,000  per  e.mm.,  while  in  a  case  exam- 
ined by  J.  N.  Hall2  the  hemoglobin  was  200  per  cent,  (making 
it  necessary  to  dilute  the  blood  doubly  in  order  to  make  the  test 
with  the  von  Fleischl  hemometer),  and  the  erythrocyte  count 
reached  9,949,600.  Estimates  not  differing  greatly  from  these 
have  also  been  reported  by  Cabot,3  Saunby  and  Russell,4  C.  G. 
Stockton,5  Turk,6  Vaquez  and  Quiserne,7  and  others.  The 
blood  is  thick  and  tarry,  flows  sluggishly  from  the  puncture, 
and  coagulates  with  great  rapidity.  The  cause  of  the  enor- 
mous polycythemia  is  a  moot  point.  Osier8  proposes  as  a 
factor  hyperviscosity  of  the  blood,  in  consequence  of  which  the 
intracapillary  flow  is  impeded.  Gibson9  attributes  it  to  peripheral 
stasis  dependent  upon  myocardial  weakness. 

Osier's  disease,  as  it  may  be  fittingly  termed,  occurs  in  middle 
age,  and,  aside  from  the  blood  findings,  is  characterized  by  idio- 
pathic and  permanent  cyanosis,  by  splenic  and  sometimes  hepatic 
enlargement,  and  almost  invariably  by  albuminuria.  In  the  cases 
thus  far  studied  no  clinically  demonstrable  lesion  of  the  heart  or 
lungs  has  accounted  for  the  cyanosis,  nor  has  autopsy  revealed 
tuberculosis  of  the  spleen,  which  in  its  primary  form  is  associated 
with  cyanosis  and  polycythemia  of  a  moderate  degree. 

The  leucocytes  are' usually  not  increased,  although  in  an  occa- 
sional instance  they  have  been  found  to  number  about  double  the 
maximum  normal  standard.    Differentially  they  are  also  normal. 


XVII.  DENGUE. 

Graham,10  of  Beyrouth,  recently  announced  that  dengue  is  due 
to  a  protozoon  resembling  in  some  respects  the  malarial  parasite. 
He  believes  that  such  an  organism  is  constantly  present  in  the  dis- 
ease, and  that  it  undergoes  an  evolution  within  the  erythrocytes  at 
their  expense.  Furthermore,  it  is  held  that  the  parasite  is  harbored 
and  conveyed  by  a  species  of  mosquito,  the  Culex  fatigans. 
Graham's  work  still  lacks  confirmation,  and  hence  cannot  be 

1  Amer.  Jour.  Med.  Sci.,  1903,  vol.  exxvi,  p.  187. 

2  Amer.  Med.,  1903,  vol.  v,  p.  1026. 

3  Boston  Med.  and  Surg.  Jour.,  1899,  vol.  cxli,  p.  574;  ibid.,  1900,  vol  cxlii 
P-2745- 

4  Loc.  cit.  s  Medical  News,  1903,  vol.  Ixxxii,  p.  948. 
Cited  by  Osier,  loc.  cit.                    7  Sem.  med.,  1902,  vol.  xxii,  p.  235. 

8  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  121. 

9  Lancet,  1903,  vol.  ii,  p.  1560.  10  Med.  Rec,  1902,  vol.  Ixi,  p.  204. 


DIABETES  MELLITUS. 


383 


considered  conclusive.  Study  of  the  corpuscles  in  this  disease 
seems  to  have  been  generally  neglected. 

XVIII.  DIABETES  MELLITUS. 

The  alkalinity  of  the  blood,  according  to  the 
General     investigations  of    Minkowski,1   is  appreciably 
Features,     diminished,  especially  in  cases  in  which  coma 
either  impends  or  exists.    The  change,  however, 
cannot  be  regarded  as  constant,  since  in  none  of  the  five  cases 
lately  studied  by  Golla2  did  the  alkalinity  figures  differ  materially 
from  normal. 

Orlowsky3  in  two  cases  of  diabetes  mellitus  appreciably  in- 
creased the  blood  alkalinity  by  giving  warm  alkaline  enemata, 
the  change  thus  effected  being  more  decided  and  persisting  longer 
than  when  caused  by  the  administration  of  similar  drugs  by  the 
mouth.  He  believes  in  treating  diabetic  coma  in  this  manner, 
the  alkali  being  given  for  some  time  after  urgent  symptoms  have 
disappeared.  Lipemia  is  not  uncommon,  the  amount  of  fat  in 
some  instances  being  so  large  as  to  produce  a  milky  appearance 
of  the  blood  drop,  evident  to  the  naked  eye,  although  in  most 
instances  the  condition  is  recognizable  only  by  the  detection  of 
fat  globules  under  the  microscope.  Not  infrequently  diabetic 
blood  has  a  peculiar  salmon  color.  Neisser  and  Derlin4  report  a 
case  of  diabetes  which  showed  20  per  cent.  (!)  of  fat  in  the  in- 
spissated blood  obtained  by  venesection.  Lipacidemia  may 
be  detected  in  diabetic  coma.  Glycemia  is  present,  and  can  be 
demonstrated  by  the  detection  of  grape-sugar  in  relatively  large 
amounts,  even  as  great  as  5.7  parts  per  thousand,  according 
to  Grawitz,5  or  9  per  thousand,  according  to  Hoppe-Seyler.6  (See 
p.  141.) 

Williamson's  Test. — This  reaction,  devised  by  Williamson7  in 
1896,  depends  upon  the  fact  that  a  warm  alkaline  solution  of 
methylene-blue  is  decolorized  when  mixed  with  a  minute  quantity 
of  glucose.  Twenty  c.mm.  of  the  suspected  blood,  obtained 
by  puncturing  the  finger,  are  measured  by  means  of  Gower's 
hemocytometer  pipette,  and  blown  out  into  40  c.mm.  of  distilled 
water  "contained  in  a  small  test-tube.    To  this  mixture  are  then 

1  Mitth.  a.  der  med.  Klinik.  z.  Konigsberg,  1888. 

2  Lancet,  1903,  vol.  i,  p.  1230. 

3  Russkiy  Vrach,  1901,  vol.  xxii,  pp.  1190  and  1222. 

4  Zeitschr.  f.  klin.  Med.,  1904,  vol.  li,  p.  428. 

5  Loc.  cit.  6  Virchow's  Arch.,  1858,  vol.  xiii,  p.  104. 
7  Brit.  Med.  Jour.,  1896,  vol.  ii,  p.  730;  also  Lancet,  1900,  vol.  ii,  p.  320. 


384 


( ;  K  N  K  R  A  L  II  KM  ATOLOG  Y . 


added,  in  the  order  given,  i  c.c.  of  a  i :  6000  aqueous  solution  of 
methylene-blue  and  40  c.mm.  of  a  six  per  cent,  aqueous  solution  of 
potassium  hydrate.  In  a  second  test-tube  the  same  proportions  of 
normal  blood  and  reagents  are  mixed,  to  be  used  as  a  control. 
The  color  of  both  mixtures  is  precisely  the  same — moderately  deep 
bluish-green.  Both  tubes  are  placed  in  a  beaker  filled  with  boil- 
ing water,  in  which  they  are  allowed  to  remain  for  four  minutes, 
at  the  end  of  which  time  the  test  fluid  containing  the  diabetic 
blood  will  have  turned  a  dingy  yellow  color,  while  the  color  of 
the  control  mixture  remains  unchanged.  Care  must  be  taken  to 
use  not  more  than  20  c.mm.  of  blood,  since  a  positive  reaction 
may  be  more  or  less  closely  counterfeited  with  non-diabetic  blood 
should  three  or  four  times  this  quantity  be  employed.  It  is 
essential,  therefore,  to  measure  the  blood  accurately,  and  not  to 
trust  to  the  approximate  method  used  by  some,  of  simply  taking 
two  drops  of  blood  as  the  equivalent  of  the  required  20  c.mm. 

Williamson's  reaction  is  presumably  due  solely  to  the  action  of 
the  grape-sugar  contained  in  diabetic  blood,  and  if  this  proves 
true,  it  is  not  unreasonable  to  predict  that  the  principle  of  the  test 
may  be  elaborated  into  a  method  for  estimating  the  percentage 
of  sugar  in  the  blood.  Positive  reactions  occur  constantly  in 
diabetes,  sometimes  even  after  the  disappearance  of  every  trace 
of  sugar  from  the  urine,  and,  so  far  as  investigations  up  to  the 
present  time  have  shown,  negative  results  are  invariably  met  with 
in  other  diseases. 

Bremer's  Test. — Bremer/  having  noticed  in  diabetes  mellitus 
peculiar  affinities  of  the  erythrocytes  for  various  anilin  dyes,  has 
devised  upon  this  basis  an  ingenious  test  for  the  recognition  of 
diabetic  blood.  Several  thick  films  from  a  suspected  case,  con- 
trolled by  the  same  number  of  preparations  made  from  normal 
blood,  are  prepared,  preferably  on  slides,  and  heated  in  an  oven 
to  a  temperature  of  1350  C,  after  which  they  are  set  aside  to 
cool.  Both  sets  of  films  are  then  stained  for  about  two  minutes 
with  a  one  per  cent,  aqueous  solution  of  Congo-red  (mixed  freshly 
just  before  using),  thoroughly  washed  in  running  water,  and 
dried  between  bits  of  filter-paper.  Thus  treated,  diabetic  blood 
is  either  colored  pale  greenish-yellow  or  is  entirely  unstained, 
while  normal  blood  stains  typically  the  red  color  of  the  dye. 
Using  the  same  method  of  heat  fixation,  other  anilin  dyes  may 
be  employed  to  demonstrate  this  peculiar  behavior  of  diabetic 
blood.  For  example,  with  a  one  per  cent,  aqueous  solution  of 
methylene-blue  the  diabetic  specimen  stains  yellowish-green  and 

1  N.  Y.  Med.  Jour.,  1896,  vol.  Ixiii,  p.  301  {Lit.);  also  Med.  Record,  1897, 
vol.  xii,  p.  495- 


DIABETES  MELLITUS. 


3*5 


the  normal  Mm  blue.  Diabetic  blood,  on  the  contrary,  treated 
with  a  one  per  cent,  aqueous  solution  of  bicbrich-scarlet,  takes 
the  color  of  the  dye  in  a  typical  manner,  while  normal  blood  re- 
mains practically  uncolored.  Ehrlich's  triacid  stain,  as  well  as 
mixtures  of  methylene-blue  and  eosin  and  methyl-green  and 
eosin,  have  also  been  used  to  demonstrate  the  reaction.  _  The 
cause  of  Bremer's  reaction  is  unknown,  but  apparently  it  is  not 
due  to  the  effect  of  glucose;  many  authors  are  inclined  to  attrib- 
ute it  to  excessive  acidity  of  the  blood.  Positive  results  with 
this  test  cannot  be  regarded  as  pathognomonic  of  diabetes  mel- 
litus,  since  they  have  been  reported  with  the  blood  of  persons  suf- 
fering from  exophthalmic  goiter,  multiple  neuritis,  leukemia,  and 
Hodgkin's  disease. 

There  are  no  constant  changes  to  be  found 
Hemoglobin  in  these  elements.    Normal  hemoglobin  percent- 
and         ages  and  erythrocyte  counts  are  observed  in 
Erythrocytes,  most  cases,  while  in  others  in  which  the  cachexia 
is  pronounced  a  well-marked  secondary  anemia 
may  exist.    James,1  in  a  study  of  13  cases,  found  the  number 
of  erythrocytes  over  6,000,000  in  5;  5,000,000  plus  in  5;  4,000,- 
000  plus  in  2;  and  3,000,000  plus  in  1.    The  hemoglobin  per- 
centage was  over  100  in  3  cases;  60-70  in  8;  and  50-60  in  2.  The 
alterations  in  the  hemoglobin  and  erythrocytes  in  diabetes  have 
been  attributed  by  the  older  writers  2  chiefly  to  the  effects  of  blood 
concentration  and  dilution.    Thus,  it  was  believed  that  in  cases 
with  excessive  polyuria  the  blood  became  inspissated  and  the 
count  thus  increased,  while  in  cases  with  pronounced  glycemia 
the  blood  became  diluted  and  the  count  lowered  as  a  consequence 
of  the  fluid  transfer  from  the  tissues  into  the  capillaries  provoked 
by  the  presence  in  the  blood  of  a  large  percentage  of  sugar.  It 
is  obvious  that  these  influences,  if  active,  are  sufficient  to  render 
the  blood  count  in  diabetes  of  little  or  no  practical  value,  since, 
on  the  one  hand,  perfectly  normal  blood,  if  diluted,  may  appear 
anemic,  while,  on  the  other  hand,  anemic  blood,  if  concentrated, 
may  seem  normal.    James3  contends,  however,  that  the  poly- 
cythemia is  real,  and  is  not  dependent  upon  inspissation,  for 
were  the  increase  merely  relative,  it  would  naturally  be  accom- 
panied by  an  increase  in  the  density  of  the  blood,  and  this  in  his 
experience  never  occurred,  the  specific  gravity  figure  for  his 
series  ranging  between  1.054  and  1.060. 

1  Edinburgh  Med.  Jour.,  1896,  vol.  xlii,  p.  193. 

2  Lit.  cited  by  Leichtenstern,  "Unters.  iiber  d.  Hg-Gehalt  d.  Blutes,"  Leipsic, 
1878. 

3  Loc.  cit. 

25 


386 


GENERAL  HEMATOLOGY. 


High  digestion  leucocytosis  is  the  most  con- 
LEUCOCYTES.  stant  change  affecting  these  cells,  but  this  is  not 
found  in  every  case.  Isolated  examples  of  leu- 
cocytosis, apparently  independent  of  this  influence,  have  been  re- 
ported, but  in  the  great  majority  of  diabetics  the  leucocyte  count 
is  normal.  The  presence  of  small  numbers  of  myelocytes  in 
cachectic  patients  is  the  only  qualitative  change  to  which  atten- 
tion has  been  directed.  Mahogany-colored  granules,  either  within 
the  leucocytes  or  extracellular,  may  usually  be  demonstrated  by 
the  iodin  method.  No  numerical  change  in  the  blood  plaques  has 
been  reported. 

Williamson's  reaction  is  of  real  value,  es- 
Diagnosis.    pecially  in  the  recognition  of  cases  with  temporary 
disappearance  of  sugar  from  the  urine  and  in 
diabetic  coma.  ,  Bremer's  test  and  the  iodin  reaction  are  to  be 
regarded  as  symptomatic,  not  necessarily  of  diabetes.    The  other 
blood  findings  are  without  diagnostic  value. 


XIX.  DIPHTHERIA. 

Usually  the  changes  in  the  hemoglobin  and 
Hemoglobin  erythrocytes  are,  at  the  most,  trifling,  for  in 
and  about  two-thirds  of  all  cases  these  elements  are 
Erythrocytes,  practically  normal,  while  in  the  other  one-third 
moderate  anemia,  more  marked  in  severe  than 
in  mild  cases,  is  found.  The  anemia  does  not  develop  until 
about  the  middle  of  the  first  week  of  the  disease,  and  is,  as  a 
rule,  characterized  by  a  diminution  of  hemoglobin  roughly  pro- 
portionate to  the  corpuscular  loss.  Degenerative  changes  are  rare, 
consisting  usually  of  nothing  more  than  occasional  polychromato- 
philia;  nucleation  and  deformities  of  size  and  of  shape  are  absent. 
Regeneration  of  the  blood  takes  place  slowly,  and,  as  the  loss  of 
hemoglobin  is  made  up  less  rapidly  than  that  of  the  corpuscles, 
the  color  index,  which  is  approximately  normal  early  in  the  dis- 
ease, later  falls  considerably. 

The  loss  of  hemoglobin  does  not  often  exceed  15  per  cent., 
nor  is  the  decrease  of  erythrocytes  usually  greater  than  from 
500,000  to  750,000  cells  to  the  c.mm.  Concentration  of  the 
blood,  which  frequently  occurs  during  the  febrile  period,  may 
cause  striking  temporary  polycythemia. 

Morse,1  in  single  examinations  of  30  cases  treated  without 
antitoxin,  found  the  count  of  erythrocytes  above  5,000,000  in 

1  Boston  Med.  and  Surg.  Jour.,  1895,  vol.  cxxxii,  pp.  228  and  252. 


DIPHTHERIA. 


387 


21,  and  below  4,000,000  in  but  a  single  instance,  a  woman  with 
chronic  anemia;  several  of  his  counts  were  in  the  neighborhood 
of  6,000,000.  From  this  author's  monograph1  the  following 
counts  reported  by  other  investigators  are  taken:  Bouchut 
and  Dubroisay,2  4,305,000  as  the  mean  average  of  93  counts  in 
84  cases;  Gilbert,3  an  average  of  4,500,000  in  58  counts  in  22 
cases;  Carter,4  an  average  of  4,253,000  in  13  cases;  and  File,5  an 
average  of  4,588,000  in  18  counts  in  10  cases,  some  of  which  had 
received  antitoxin.  Billings,6  in  a  painstaking  study  of  7  cases 
untreated  with  antitoxin,  in  which  36  counts  were  made,  found  a 
moderate  but  distinct  decrease  in  hemoglobin  and  erythrocytes 
in  5  cases,  the  loss  first  becoming  apparent  by  the  third  or  fourth 
day,  and  being  proportionate  to  the  severity  of  the  infection. 
This  author's  first  counts,  all  made  during  the  first  week  of  the 
disease,  ranged  from  5,200,000  to  6,122,000,  the  average  being 
5,611,285,  the  hemoglobin  for  the  same  period  ranging  from  70 
to  98  per  cent,  and  averaging  90  per  cent.  Subsequent  counts 
in  this  series  showed  that  the  greatest  loss  of  hemoglobin  averaged 
12  per  cent.,  ranging  from  1  to  30  per  cent.,  and  that  the  maximum 
corpuscular  loss  averaged  878,500,  varying  from  227,000  to  2,040,- 
000. 

It  is  generally  observed  that  in  cases  treated  with  antitoxin 
the  anemia  is  decidedly  less  than  in  those  treated  by  other 
methods,  and,  in  fact,  a  majority  of  cases  thus  treated  suffer  no 
decrease  at  all. 

Well-marked  leucocytosis,  beginning  probably 
Leucocytes,  within  a  few  hours  after  the  infection  first  occurs, 
characterizes  the  average  case  of  diphtheria  of 
moderate  severity.  An  analysis  of  the  statistics  derived  from  276 
counts  made  by  reliable  investigators7  shows  that  over  90  per 
cent,  of  all  cases  are  accompanied  by  a  more  or  less  marked 
increase  in  the  number  of  leucocytes. 

In  the  majority  of  cases  the  number  of  leucocytes  is  not  in- 
creased above  30,000  per  c.mm.,  but  a  much  greater  leucocytosis 
is  sometimes  encountered.  Thus,  the  maximum  counts  of  several 
authors  are  as  follows:  Felsenthal,  148,229s;  Ewing,  72,000*; 

1  Med.  and  Surg.  Reports  of  the  Boston  City  Hospital  1899,  tenth  series, 
p.  138. 

2  Compt.  rend.  Soc.  biol.,  Paris,  1877,  vol.  lxxxv,  p.  158. 

3  Traite  de  Med.  Charcot-Bouchard,  vol.  ii,  p.  485. 

4  Univ.  Med.  Mag.,  1894-95,  vol.  vii,  pp.  17,  81.  and  158. 

5  Lo  Sperimentale,  1896,  vol.  1,  p.  284.       6  Med.  Record,  1896,  vol.  xlix,  p.  577. 

7  Ewing,  Morse,  Billings,  Carter,  Schlesinger,  File,  Gabritschewsky,  Bouchut 
and  Dubroisay,  Rieder,  Felsenthal,  and  Gilbert. 

8  Arch.  f.  Kinderheilk.,  1893,  vol.  xv,  p.  78. 

9  N.  Y.  Med.  Jour.,  1893,  vol.  lviii,  p.  713. 


388 


GENERAL  HEMATOLOGY. 


Gabritschewsky,  51,00c1 ;  Morse,  48,ooo2;  Carter,  48,28c3;  Billings, 
38,600";  and  Gilbert,  31,000.° 

This  increase  is  to  be  regarded  as  a  rough  gage  of  the  reac- 
tion of  the  individual  against  the  effects  of  the  toxic  products  of 
the  disease ;  it  is,  therefore,  absent  in  very  mild  cases,  where  little 
or  no  reaction  is  excited,  and  in  severe  cases  in  which  the  patient's 
resisting  powers  are  overwhelmed  by  the  intoxication. 

In  favorable  cases  the  maximum  leucocytosis  is  reached  coin- 
cidental^ with  the  height  of  the  disease,  and  the  increase  gradually 
fades  away  during  convalescence,  having  in  most  cases  entirely 
ceased  by  the  time  the  membrane  has  disappeared,  but  occa- 
sionally persisting  after  the  subsidence  of  all  local  and  systemic 
manifestations  of  the  illness.  In  unfavorable  cases  high  leucocyte 
counts  persist  until  death,  or  "in  somewhat  prolonged  cases, 
with  much  septic  absorption,  there  may  be  an  uninterrupted 
decrease  of  leucocytes  continuing  up  to  the  fatal  termination" 
(Ewing).  No  constant  relation  has  been  determined  between  the 
leucocytosis  and  the  extent  of  the  local  lesion,  the  degree  of  ton- 
sillar and  glandular  swellings,  or  the  height  of  the  fever,  although 
in  individual  cases  some  authors  have  suggested  that  such  relation- 
ship may  be  distinguished. 

The  effects  of  antitoxin  upon  the  leucocytes  are  well  illustrated 
by  the  conclusions  of  Ewing,6  based  upon  228  counts  made  in  53 
cases  before  and  after  the  injection  of  the  serum.  As  the  result 
of  these  investigations  this  author  concludes  that  antitoxin,  within 
thirty  minutes  after  its  injection,  causes  a  hypoleucocytosis.  In 
favorable  cases,  after  the  injection,  the  original  height  of  the 
leucocytosis  is  not  again  attained,  but  in  severe  and  less  favor- 
able cases  the  dose  of  antitoxin  is  followed  in  a  few  hours  by 
a  hyperleucocytosis  exceeding  that  found  in  the  primary  count. 
In  malignant  cases  the  administration  of  antitoxin  may  be  fol- 
lowed immediately  either  by  rapid  hyperleucocytosis  or  by  ex- 
treme hypoleucocytosis  and  death.  Bize7  finds  that  in  some 
cases  the  initial  serum  injection  may  not  affect  the  leucocytes  be- 
cause of  the  insufficiency  of  the  dose,  and  that  repeated  injections 
are  sometimes  required  to  modify  the  count.  This  investigator 
has  also  called  attention  to  the  pronounced  leucocytoses  which 
accompany  eruptions  due  to  antitoxin. 

The  leucocytosis  of  diphtheria,  as  a  rule,  involves  the  polynu- 
clear  neutrophile  cells,  most  cases  showing  about  80  per  cent, 
of  this  variety,  but  in  an  occasional  instance  there  may  be  a 


1  Annal.  de  l'lnstitut  Pasteur,  1894,  vol.  viii,  p.  673.  2  Loc.  cit. 

3  Loc.  cit.  4  Loc.  cit.  5  Loc.  cit. 

6  Loc.  cit.  7  Arch,  de  med.  des  Enf.,  1901,  vol.  iv,  p.  102. 


DIPHTHERIA. 


389 


well-marked  increase  in  the  mononuclear  forms,  considerably  in 
excess  of  the  percentage  found  in  health.  Relative  lymphocy- 
tosis has  been  observed  both  during  convalescence  and  in  fatal 
casts  with  leucopenia,  and  absolute  lymphocytosis  may  occur  at 
the  height  of  the  disease  in  cases  with  high  total  leucocyte  counts. 
In  two  of  Ewing's  cases  1  the  estimates  showed  60  per  cent,  of 
lymphocytes  in  a  count  of  72,000  leucocytes,  and  62  per  cent,  of 
these  cells  in  a  count  of  22,500. 

Besredka2  believes  that  marked  polynuclear  leucocytosis  is  a 
good  prognostic  sign,  especially  if  this  form  of  cells  shows  a 
strong  tendency  to  increase  after  injection  of  antitoxin.  On  the 
contrary,  cases  which  fail  to  show  such  a  change  he  regards  as 
grave,  usually  as  fatal.  This  characteristic  of  high  percentages 
of  polynuclear  neutrophiles  is  also  regarded  by  many  other  authors 
as  a  favorable  clinical  sign,  and  a  low  percentage  as  unfavorable. 

Ewing,3  by  staining  the  leucocytes  with  gentian-violet  (50  c.c. 
of  normal  salt  solution  to  which  one  drop  of  a  saturated  alcoholic 
solution  of  gentian- violet  is  added),  has  deduced  certain  conclu- 
sions from  the  reaction  of  the  leucocytes  to  this  dye,  to  which  he 
is  inclined  to  attribute  great  prognostic  value.  He  believes  that 
the  numbers  and  percentages  of  poorly  stained  leucocytes,  and 
usually  of  ameboid  figures,  invariably  increase  in  unfavorable 
cases,  without  relation  to  the  total  number  of  cells  found  in  the 
blood.  In  his  experience  any  considerable  increase  of  poorly 
stained  leucocytes,  especially  if  associated  with  a  decrease  of  the 
well-stained  cells,  was  invariably  the  forerunner  of  a  grave  or 
fatal  change  in  the  patient's  condition.  In  favorable  cases,  after 
treatment  with  antitoxin,  he  noted  that  the  polymorphous  forms 
show  a  decidedly  increased  affinity  for  gentian-violet,  this  char- 
acteristic often  being  observed  within  twelve  hours  after  the  in- 
jection of  the  serum.  Failure  of  this  peculiarity  to  develop  he 
regards  as  a  very  unfavorable  prognostic  sign. 

The  proportion  of  eosinophiles  is  exceedingly  variable,  these 
cells  sometimes  being  absent,  and  at  other  times  found  in  large 
numbers— four  or  five  per  cent.  Kucharzewski 4  concludes,  from 
experimental  work  with  animals,  that  a  high  percentage  of  eosino- 
philes is  of  favorable  prognosis  and  that  a  low  percentage  is  unfavor- 
able. 

Engel5  found  variable  percentages  of  myelocytes  in  both  favor- 

1  "  Clinical  Pathology  of  the  Blood,"  2d  ed.,  New  York  and  Philadelphia,  1904. 

2  Annal.  de  l'Institut  Pasteur,  1898,  vol.  xii,  p.  305. 

3  N.  Y.  Med.  Jour.,  1893,  vol.  lviii,  p.  713. 

4  XIV.  Internat.  Med.  Congress,  Madrid,  Apr.  23-30,  1903;  abst.,  Jour.  Amer. 
Med.  Assoc.,  1903,  vol.  xl,  p.  1673. 

5  Deutsch.  med.  Wochenschr.,  1897,  vol.  xxiii,  pp.  118  and  137. 


39° 


GENERAL  HEMATOLOGY. 


able  and  unfavorable  cases,  especially  in  the  latter,  and  he  con- 
siders their  presence  in  relatively  high  percentages  (2  per  cent, 
or  higher)  as  an  unfavorable  prognostic  indication.  In  7  of 
Engel's  fatal  cases  the  percentage  of  myelocytes  ranged  from  3.6 
to  14.6,  but  they  never  exceeded  1.5  per  cent,  in  patients  who 
recovered.  An  absence  of  myelemia,  however,  is  no  guarantee 
of  recovery,  for  this  sign  is  absent  in  about  one  out  of  every  four 
fatal  cases. 

Examination  of  the  blood  in  diphtheria  gives 
Diagnosis,    no  information   which  is   not   clearly  shown 
by  other  clinical  signs,  and  it  must  be  regarded 
as  of  no  value  as  an  aid  to  diagnosis.    The  leucocytosis  in  this 
disease,  if  the  very  benign  and  the  very  severe  cases  are  excluded, 
is,  as  a  rule,  proportionate  to  the  intensity  of  the  infection. 

From  a  prognostic  point  of  view  it  appears  that,  as  in  pneu- 
monia, an  absence  of  leucocytosis  occurring  in  obviously  severe 
infections  is  an  unfavorable  indication.  The  presence  of  a  large 
percentage  of  myelocytes  has  a  similar  meaning.  Pronounced 
lymphocytosis  is  also  regarded  as  an  unfavorable  prognostic 
sign. 

XX.  ENTERITIS. 

In  acute  catarrhal  enteritis  the  same  changes 
Enteritis     occur  that  are  found  in  acute  gastritis,  namely, 
and         little  or  no  alteration  in  the  hemoglobin  and 
Diarrhea,    erythrocytes,  and  an  inconstant,  moderate  leuco- 
cytosis.   Profuse  watery  dejecta  lead,  of  course, 
to  more  or  less  blood  concentration,  by  depletion  of  the  body- 
fluids,  and  hence  polycythemia  may  be  a  transient  sign.    In  the 
summer  diarrheas  of  infants  Knox  and  Warfield1  found  that  the 
leucocyte  count,  although  usually  increased,  varies  so  widely  that 
the  mere  presence  of  a  high  or  a  low  count  is  of  practically  no 
definite  diagnostic  importance.    An  increase  in  the  relative  per- 
centage of  polynuclear  neutrophils,  even  with  a  normal  number 
of  leucocytes,  suggests  the  onset  of  inflammatory  intestinal  com- 
plications.   These  findings  Zahorsky  has  fully  corroborated.2  In 
chronic  enteritis  and  in  gastro- enteritis  the  interference  with  the 
patient's  nutrition  plus  a  drain  upon  the  albuminoids  may  in 
course  of  time  give  rise  to  a  decided  anemia.    Leucocytosis  is  not 
a  characteristic  of  such  cases. 

1  Johns  Hopkins  Hosp.  Bull.,  1902,  vol.  xiii,  p.  167. 

2  N.  Y.  Med.  Jour.,  1903,  vol.  lxxviii,  p.  505. 


ENTERITIS. 


39 1 


In  dysentery  and  in  ulcerative  and  phlegmon- 
Dysentery.    ous  enteritis  acute  forms  of  secondary  anemia  are 
frequently  met  with,  especially  in  patients  who 
pass  much  blood  by  the  bowel.    Leucocytosis,  often  of  high 
degree,  is  also  common  in  these  lesions. 

In  38  cases  of  uncomplicated  amebic  dysentery  Futcher 1  found 
that  the  hemoglobin  averaged  63  per  cent,  and  the  erythrocytes 
4,802,000  per  c.mm.,  while  in  43  cases  the  leucocytes  averaged 
10,600.  In  15  cases  complicated  by  amebic  abscess  of  the  liver  the 
hemoglobin  averaged  66  per  cent.,  the  erythrocytes  4,250,000,  and 
the  leucocytes  18,350.  Doubtless  in  both  series  the  high  erythro- 
cyte values  may  be  referred  to  blood  concentration.  The  value  of 
the  leucocyte  count  in  the  diagnosis  of  amebic  hepatic  abscess  is 
doubtful.  In  most  abscess  cases,  such  as  in  the  n  reported  by 
Schlayer,2  the  leucocytosis  is  high  (averaging  in  this  series  25,000 
and  ranging  between  18,000  and  62,000);  but  in  other  cases  low 
counts  (6000,  9000,  and  11,000  in  Osier's  series3)  are  not  incom- 
patible with  pus.  In  Rogers'  experience4  the  count  is  higher  in 
small,  deeply  seated  abscesses  than  in  those  superficially  situated. 
In  differentiating  malarial  fever  from  the  intermittent  pyrexia  of 
hepatic  abscess  the  presence  of  leucocytosis  practically  excludes  the 
former. 

As  a  means  of  differentiating  amebic  from  bacillary  dysentery 
the  serum  test  is  of  value,  for  the  Bacillus  dysenteric  is  clumped 
by  the  blood  of  persons  suffering  from  bacillary  (Shiga5)  dysentery, 
but  not  by  the  blood  of  those  infected  with  the  amebic  form  of  the 
disease.  Rogers6  has  used  the  test  extensively  in  India  with  great 
success. 

On  similar  grounds  it  may  be  presumed,  until  proof  to  the 
contrary  is  shown,  that  Shiga's  organism  is  unaffected  by  the 
blood  of  those  infected  with  so-called  dysentery  due  to  the  bacilli 
of  Ogata,  of  Lessage,  and  of  Roger,  and  to  the  Balantidium  coli. 

Shiga's  claim,7  that  the  Bacillus  dysenteries  is  never  clumped 
by  the  blood  of  non-dysenteric  diseases,  needs  revision,  in  the 
light  of  the  researches  of  Park,8  Pilsbury,9  and  Strong.10 
These  observers  have  found  that  dysentery  bacilli  of  the 
Shiga,  the  Flexner,  and  the  Kruse  strains  occasionally  clumped 
with  the  blood  of  persons  suffering  from  such  diseases  as  alcoholic 

1  Jour.  Amer.  Med.  Assoc.,  1903,  vol.  xli,  p.  480. 

2  Munch,  med.  Wochenschr.,  1903,  vol.  1,  p.  i372- 

3  Med.  News,  1902,  vol.  lxxx,  p.  673.  4  Brit.  Med.  Jour.,  1902,  vol.  ii,  p.  850. 
5  Centralbl.  f.  Bakt.  u.  Parasit.,  1898,  vol.  xxiii,  p.  599. 

0  Brit.  Med.  Jour.,  1903,  vol.  i,  p.  13 15. 

7  Loc.  cit.  8  Jour.  Med.  Research,  1903,  vol.  ix,  p.  180. 

9  Med.  News,  1903,  vol.  lxxxiii,  p.  1078.        10  Rep.  Surg.-Gen.,  U.  S.  A.,  1900. 


392 


GENERAL  HEMATOLOGY. 


enteritis,  tuberculosis,  enteric  fever,  appendicitis,  pernicious 
anemia,  and  pleurisy— even  in  dilutions  as  high  as  1:30,  1:50, 
and  1:100.  Still,  it  is  safe  to  regard  a  positive  reaction  with  the 
Bacillus  dysenterice  as  the  most  valuable  single  clinical  sign  of 
acute  bacillary  dysentery  in  adults  in  whom  a  recent  chronic  in- 
flammation of  the  intestine  can  be  ruled  out.  The  test,  to  be 
dependable,  should  be  made  with  at  least  a  1:20  dilution,  the 
time-limit  being  not  more  than  two  hours.  Pilsbury  found 
that  false  positive  reactions  do  not  occur  with  the  blood  of  non- 
dysenteric  children  under  one  year  of  age. 

Attempts  to  isolate  organisms  by  bacteriologi- 
Sprue.       col  examination  of  the  blood  were  unsuccessful 
in  Goadby's  hands,1  although  the  most  careful 
methods  were  employed. 

The  hemoglobin  and  erythrocytes  are  markedly  reduced,  and 
in  a  remarkably  short  time  after  the  onset  of  the  acute  symptoms 
the  cellular  loss  becomes  so  severe  as  to  simulate  that  of  true 
pernicious  anemia.  Counts  of  between  1,000,000  and  2,000,000 
were  found  to  be  the  rule  by  Bassett-Smith,2  with  correspondingly 
low  hemoglobin  values.  There  are  also  decided  structural  changes 
in  the  erythrocytes,  many  of  which  are  deformed  in  shape  and 
size  (especially  microcytes)  and  show  unnatural  pallor.  A  few 
normoblasts,  but  no  megaloblasts,  may  be  encountered.  The 
blood  plaques  are  scanty. 

The  leucocytes,  according  to  the  last-named  writer,  are  not 
increased,  and  in  some  instances  fall  to  between  1000  and  2000 
per  c.mm.  Relative  lymphocytosis,  small-celled  in  type,  relative 
eosinophilia  (in  the  exceptional  case),  and  fractional  percentages 
of  myelocytes  are  the  other  leucocyte  findings  in  this  grave  form 
of  enteric  disease. 

The  effects  upon  the  blood  of  saline  purges  were 
Effects  of    first  determined  by  Brouardel,3  and  later  studied 
Purges.      by  Grawitz4  and  by  Hay.5    The  investigations  of 
these  authors  have  shown  that  the  administration 
of  a  purgative  dose  of  Epsom  or  Glauber  salts  is  followed  within 
about  thirty  minutes  by  an  appreciable  increase  in  the  number  of 
erythrocytes,  and  that  within  an  hour  the  count  of  these  cells  is 
fully  1,500,000  more  than  before  the  purge  was  given;  three  hours 
after  this  maximum  is  reached  the  count  is  again  normal.  When 
a  certain  degree  of  concentration  is  obtained  by  these  means,  con- 
tinued administration  of  the  salt  produces  neither  additional  con- 


1  Brit.  Med.  Jour.,  1903,  vol.  ii,  p.  644. 

2  Ibid.,  1903,  vol.  ii,  p.  641.       3  Union  med.,  1897,  vol.  xxii,  p.  405. 

4  hoc.  cit.  5  Jour.  Anat.  and  Physiol.,  1882,  vol.  xvi,  p.  435. 


ENTERIC  FEVER. 


393 


centration  nor  further  purgation.  Common  table  salt  is  also  a 
most  energetic  factor  of  blood  density,  even  more  so  than  cither 
Epsom  or  Glauber  salts.  Purgative  doses  of  jalap,  croton  oil, 
and  other  drugs  of  this  class  are  also  followed  by  more  or  less 
polycythemia. 

XXI.  ENTERIC  FEVER. 

The  alkalinity  of  the  blood  is  generally  de- 
General     creased,  a  change  which  may  be  due  partly  to  the 
Features,     effect  of  the  pyrexia  and  toxemia  and  partly  to 
the  anemia.    Dare  and  Funke1  found  subnormal 
alkalinity  figures  in  20  of  23  cases  of  enteric  fever,  but  were  unable 
to  determine  the  relationship  of  this  change  to  the  other  clinical 
manifestations.    Drouin2  also  found  similar  alkalinity  values  in 
this  infection. 

The  coagulation  time  of  the  blood  is  appreciably  diminished 
in  the  early  stages  of  typhoid,  sometimes  to  such  a  degree  as  to 
favor  intestinal  hemorrhage.  During  convalescence  the  rapidity 
of  clotting  is  decidedly  increased,  and  this  tendency  may  be  re- 
garded as  a  possible  factor  of  thrombosis.  Wright  and  Knapp3 
suggest  that  the  increased  coagulability  is  due  to  the  excessive 
amount  of  calcium  salts  present  in  the  blood  at  the  time  of  con- 
valescence, and  that  this  excess  depends  chiefly  upon  the  large 
quantity  of  lime  salts  ingested  by  a  patient  kept  on  a  milk  diet. 
These  authors  advise,  as  a  preventive  measure  against  thrombo- 
sis, partial  decalcification  of  the  milk  by  the  addition  of  sodium 
citrate  (20  to  40  gr.  to  the  pint)  as  soon  as  the  danger  of  intestinal 
hemorrhage  is  over. 

Enteric  fever  is  practically  always  a  specific 
Bacteriology,  bacteriemia,  and  the  Bacillus  typhosus  can  be 
cultured  from  the  circulating  blood  in  more  than 
75  per  cent,  of  all  cases.  From  200  to  300  c.c.  of  nutrient  broth 
sown  with  2  or  3  c.c.  of  blood  gives  satisfactory  results,  although 
some  investigators,  notably  Schottmiiller,4  prefer  to  mix  the  blood 
directly  with  melted  agar,  at  a  temperature  of  450  C,  and  to 
plate  the  inoculation,  so  as  to  get  some  idea  of  the  number  of 
colonies  grown. 

The  typhoid  bacteriemia  usually  develops  early  in  the  disease, 
and  therefore  frequently  may  be  demonstrated  some  days  before 
the  appearance  of  the  serum  reaction.    Cultures  made  during  the 

1  Johns  Hopkins  Hosp.  Bull.,  1903,  vol.  xiv,  p.  175. 

2  "  Hemo-alcalimetrie  et  Hemo-acidimetrie,"  These  de  Paris,  1892,  No.  83. 

3  Brit.  Med.  Jour.,  1902,  vol.  ii,  p.  1706;  also  Lancet,  1902,  vol.  ii,  p.  1531  . 

4  Munch,  med.  Wochenschr.,  1902,  vol.  xlix,  p.  1562. 


394 


GENERAL  HEMATOLOGY. 


first  week  of  the  fever  yield  a  higher  percentage  of  positive  results 
than  those  made  during  the  second  and  third  weeks.  With  def- 
ervescence the  bacilli  disappear  from  the  blood,  but  they  reappear 
with  a  relapse,  although  not  with  a  simple  recrudescence  of  the 
fever — a  significant  fact  when  the  question  arises  of  determining 
the  presence  of  a  true  reinfection.  It  is  the  general  experience  that 
the  severer  the  type  of  the  infection,  the  more  abundant  the 
bacteria  in  the  blood.  The  following  tabulation  illustrates  the 
frequency  of  positive  results  in  cases  examined  by  modern  methods : 


A                          Number  of  pnQTTTV1?  1?^^™  Percentage  of 

authority.                 Cas£S  .Positive  Results.         Positive  Results. 

Schottmiiller  1  212  182  86  percent. 

Hewlett2   125  90  72     "  " 

Courmont;  Lesieur 3  ..57  54  95'    "  " 

Harris;  Kerr 4                 56  31  55     "  " 

Busquet 5   43  43  100     "  " 

Warfield  6  ',              43  33  76.5  "  " 

Kiihnau7                        41  11  27     "  " 

Lesieur 8                         36  36  100     "  " 

Reudiger 9                        27  20  74     "  " 

Cole 10                            15  11  73     "  " 

Castellani11                    14  12  86  " 

Orlovsky12                      12  10  83     "  " 

Auerbach;  Unger 13  10  7  70     "  " 

Courmont 14                      9  9  100     "  " 

Total:                700  549  Average:  78.4  per  cent. 


Coleman  and  Buxton's  analysis15  of  453  collected  cases  shows 
the  following  results  of  blood  culturing  during  the  first  four  weeks 
of  the  fever: 

w  Fttwu  Number  of  Cases  Per  Cent. 

Week  of  *ever.  Cases_  Positive.  Positive. 

First                              85  79  93  per  cent. 

Second  198  151  76    "  " 

Third  115  65  56    "  " 

Fourth                           55  18  33    "  " 

During  recent  years  numerous  instances  of  paracolon  (para- 
typhoid) infection,  clinically  counterfeiting  typical  enteric  fever, 

1  Munch,  med.  Wochenschr.,  1902,  vol.  xlix,  p.  1562. 

2  Med.  Rec,  1901,  vol.  lx,  p.  849.  3  Sem.  med.,  1902,  vol.  xx,  p.  408. 

4  Jour.  Amer.  Med.  Assoc.,  1902,  vol.  xxxix,  p.  1000. 

5  Presse  med.,  1902,  vol.  1,  p.  593. 

6  Bull.  Ayer  Clin.  Lab.,  Penna.  Hosp.,  1903,  vol.  i,  p.  77. 

7  Zeitschr.  f.  Hyg.  u.  Infectionskr.,  1897,  vol.  xxv,  p.  492. 

8  Gaz.  hebd.  de  med.  et  chir.,  1902,  vol.  xlix,  p.  1128. 

9  Medicine,  1903,  vol.  ix,  p.  258. 

10  Johns  Hopkins  Hosp.  Bull.,  1901,  vol.  xii,  p.  203. 

11  Centralbl.  f.  Bakt.  u.  Parasit.,  1902,  vol.  xxxi,  p.  477. 

12  Phila.  Med.  Jour.,  1903,  vol.  xi,  p.  959. 

13  Deutsch.  med.  Wochenschr.,  1900,  vol.  xxvi,  p.  796. 

14  Jour,  de  physiol.  et  de  path,  gen.,  1902,  vol.  iv,  p.  154. 

15  Med.  News,  1904,  vol.  lxxxiv,  p.  1046. 


ENTERIC  FEVER. 


395 


have  been  reported,  in  which  a  paracolon  bacillus  has  been 
isolated  from  the  blood  during  life.  Among  those  reporting 
such  cases  may  be  mentioned  Gwyn,1  Longcope,2  H.  W.  Allen,3 
Hewlett,4  Johnston,5  and  Libman.6  Of  60  cases  clinically  typhoid 
studied  by  Coleman  and  Buxton,7  2  yielded  blood  cultures  of  the 
Bacillus  coli  communis.  In  the  late  stages  of  the  disease  pyo- 
genic bacteria  have  been  found  in  the  blood. 

Examination  of  the  Rose  Spots. — Formerly  the  cultivation  of 
typhoid  bacilli  from  the  rose  spots  was  attended  by  indifferent 
success,  but  the  favorable  results  with  this  procedure  recently 
announced  by  a  number  of  authors  must  stamp  it  as  a  distinct  aid 
to  the  diagnosis  of  typhoid.  Neufeld,8  basing  his  experiments 
upon  the  belief  that  the  bacteria  lodge  and  multiply  in  the  spots 
protected  from  the  bactericidal  action  of  the  blood,  examined 
these  lesions  in  14  cases  and  obtained  positive  results  in  13.  His 
findings  have  been  corroborated  by  the  work  of  Curschmann,9 
who  found  the  bacilli  in  14  of  20  cases;  of  Richardson,10  whose 
results  were  positive  in  5  of  6  cases;  of  Kozarinoff,11  who  found 
positive  results  in  12  of  17  cases;  of  Seemann,12  who  reports  posi- 
tive findings  in  32  of  34  cases;  and  of  Scholz  and  Krause,13  who 
found  bacilli  in  the  spots  in  14  of  16  cases  examined.  The  latter 
investigators  emphasize  the  statement  that  the  bacilli  are  prone  to 
disappear  from  the  spots  after  from  three  to  five  days,  and  that, 
to  insure  the  best  results,  the  examinations  must  be  made  as  soon 
as  possible  after  the  appearance  of  the  roseola.  The  most  favor- 
able results  from  spot  culturing  yet  reported  are  those  of  Pollaco 
and  Gemelli14— invariably  positive  findings  in  50  consecutive 
cases.  All  investigators  agree  that,  in  the  great  majority  of  in- 
stances, spot  cultures  give  positive  results  several  days  before  the 
appearance  of  the  serum  test.  The  chief  disadvantages  to  this 
method  of  diagnosis  appear  to  be  the  absence  of  the  roseola  in 
some  cases,  its  late  development  in  others,  and  the  possibility 
of  not  always  being  able  to  distinguish  typhoid  spots  from  other 
eruptions. 

The  technic  used  by  Richardson15  is  simple,  and,  judging 

1  Johns  Hopkins  Hosp.  Bull.,  1898,  vol.  ix,  p.  54. 

2  Amer.  Jour.  Med.  Sci.,  1902,  vol.  exxiv,  p.  209. 

3  Ibid.,  1903,  vol.  exxv,  p.  96.  4  Ibid.,  1902,  vol.  exxiv,  p.  200. 
5  Ibid.,  1902,  vol.  exxiv,  p.  187.  6  Jour.  Med.  Research,  1902,  vol.  viii,  p.  1. 
7  Loc.  cit.                  8  Zeitschr.  f.  Hyg.  u.  Infectionskr.,  1899,  vol.  xxx,  p.  498. 

9  Munch,  med.  Wochenschr.,  1899,  vol.  xlvi,  p.  1597 

10  Phila.  Med.  Jour  .,  1900,  vol.  v,  p.  514. 

11  N.  Y.  Med.  Jour.,  1903,  vol.  lxxviii,  p.  196. 

12  Wien.  klin.  Wochenschr.,  1902,  vol.  xv,  p.  580. 

13  Zeitschr.  f.  klin.Med.,  1900,  vol.  xli,  p.  405. 

u  Centralbl.  f.  inn.  Med.,  1902,  vol.  xxiii,  p.  121.  15  Loc.  cit. 


39^ 


GENERAL  HEMATOLOGY. 


from  his  results,  trustworthy.  After  having  washed  the  skin  of 
the  part  with  alcohol  and  ether,  the  spot  is  frozen  with  an  ethyl*- 
chlorid  spray,  after  which  it  is  crucially  incised.  Its  substance 
is  then  removed  by  scraping  with  a  small  skin-curette,  and  trans- 
ferred to  a  tube  of  nutrient  bouillon.  A  second  tube  is  inoculated 
with  the  blood  which  collects  as  soon  as  the  effects  of  freezing 
have  worn  off,  both  cultures  being  then  incubated  and  examined 
in  the  usual  manner.  At  least  five  or  six  spots  should  be  thus 
treated  in  each  case,  and  two  tubes,  one  for  the  scrapings,  the 
other  for  the  blood  inoculation,  used  for  each  spot. 

If  blood  serum  from  a  case  of  enteric  fever  is 
Serum  Test,  mixed  with  a  broth  culture  of  the  Bacillus  typho- 
sus and  a  small  drop  of  this  mixture  placed  upon 
a  slide  and  examined  under  the  microscope,  it  will  be  observed 


Fig.  56. — A  Positive  Reaction.  Fig.  57. — A  Pseudo-reaction. 

Large  clumps  of  motionless  bacilli  sep-  A  few  small  clumps  of  bacilli  having 

arated  by  open  spaces.   The  few  bacteria  out-  impaired  motility.    Persistent  motility  of  the 

side*of  the  clumps  are  devoid  of  motility.  bacteria  in  other  parts  of  the  field. 


that  the  bacilli,  instead  of  continuing  to  dart  actively  to  and  fro 
across  the  field,  as  they  do  in  the  pure  culture,  are  attracted  to 
each  other,  lose  their  power  of  propulsion,  and  become  grouped 
together  in  large  agglutinated  clumps  of  irregular  outline,  which, 
after  the  lapse  of  a  variable  length  of  time,  become  more  and 
more  compact  and  homogeneous.  In  the  typical  positive  reaction 
the  field  of  the  microscope  shows  islands  of  clumped  bacilli, 
separated  from  each  other  by  large  open  spaces,  containing  per- 
haps a  few  isolated  organisms  the  motility  of  which  is  decidedly 
inhibited  at  first,  and  finally  entirely  lost.  If  the  clumps  are  of 
very  large  size,  they  produce  a  peculiar  grayish  mottling  of  the 
specimen  visible  to  the  naked  eye,  a  point  to  which  attention 


ENTERIC  FEVER. 


397 


was  first  directed  by  Greene.1  In  a  small  proportion  of  cases 
the  clumps  undergo  a  granular  change,  and  then  become  entirely 
destroyed;  in  some  instances  they  remain  unaltered  for  several 
days;  and  in  still  others  they  may  break  up  after  a  few  hours, 
the  field  then  becoming  refilled  with  isolated,  actively  motile 
bacteria. 

In  a  certain  percentage  of  instances  the  agglutinated,  motion- 
less masses  of  bacilli  may  be  observed  as  soon  as  the  specimen  is 
brought  into  focus,  so  that  the  reaction  may  be  said  to  have  taken 
place  immediately.  In  other  instances  some  little  time  elapses 
before  the  character  of  the  test  can  be  determined,  and  in  such 
reactions  the  formation  of  the  clumps,  from  their  inception  out 
of  two  or  three  bacteria  to  their 
completion,  when  they  consist 
of  several  hundred  organisms 
tightly  glued  together  into  a 
densely  crowded  mass,  may  be 
studied  advantageously.  In 
these  slower  reactions,  while 
early  clumping  may  progress 
to  some  extent,  many  isolated 
bacteria  are  seen,  the  motility 
of  which  persists  for  a  variable 
period,  gradually  growing  less 
and  less,  until  finally,  with 
more  or  less  crippled  powers 
of  propulsion,  the  organisms 
are  attracted  to  the  clump 
centers  with  which  they  are 
ultimately  incorporated,  either 

becoming  adherent  at  first  approach,  or,  as  is  usually  the  case 
with  the  more  active  bacilli,  circling  around  the  edges  of  the 
clump  for  some  little  time  before  becoming  attached  to  it.  Still 
other  reactions  are  characterized  by  an  almost  immediate  cessa- 
tion of  motility,  followed  by  tardy  agglutination,  and  usually  by 
the  formation  of  clumps  of  smaller  size  than  those  noted  in  a 
prompt  and  immediate  reaction. 

If  the  reaction  is  negative,  the  motility  of  the  bacilli  persists 
and  the  formation  of  clumps  is  not  observed,  regardless  of  the 
time  during  which  the  specimen  is  watched.  Not  unless  aggluti- 
nation is  marked  and  entire  loss  of  motility  occurs  may  a  reaction 
be  considered  positive ;  and  pseudo-reactions  resulting  in  the  for- 
mation of  small  masses  of  more  or  less  motile  organisms,  together 

1  Med.  Record,  1896,  vol.  1,  pp.  697  and  805. 


Fig.  58. — Bacillus  Typhi  Abdominalis. 
The  bacilli  are  actively  motile  throughout  the 
field. 


398 


GENERAL  H EM ATOLOG Y. 


with  persistent  motility  of  many  unclumped  bacteria  in  other  parts 
of  the  field,  cannot  be  regarded  as  typical  in  any  sense.  Clumping  of 
small  numbers  of  bacteria  sometimes  occurs  in  the  pure  culture 
during  its  growth,  and  this  source  of  error  must  be  eliminated  by 
habitually  examining  the  culture  before  each  test  or  series  of  tests. 

Technic. — In  order  to  exclude  all  sources  of  error,'  such  as 
may  arise  from  the  clumping  of  the  typhoid  bacillus  by  non- 
typhoid  serum,  provided  that  the  latter  is  sufficiently  concentrated 
and  is  allowed  enough  time  to  exert  its  agglutinative  powers,  the 
reaction  can  be  considered  of  diagnostic  value  only  under  the 
following  two  conditions:  first,  that  the  blood  to  be  tested  must 
always  be  diluted  with  at  least  twenty  volumes  of  the  culture;  and, 
second,  that  loss  of  motility  and  clump  formation  must  occur 
within  an  arbitrary  time  limit  of  ten  minutes.  Under  these  condi- 
tions it  has  been  shown  that  agglutination  of  the  typhoid  bacillus 
is  produced  only  by  the  blood  from  a  patient  who  is  or  who 
has  been  infected  with  enteric  fever,  save  in  exceptional  cases. 
(See  p.  403.)  In  some  cases  of  typhoid  the  reaction  occurs  in 
much  higher  dilutions,  frequently  with  dilutions  of  1:  50,  or 
1  :  ioo,  or  even  higher.  Some  habitually  work  with  higher 
dilutions  than  1  : 20,  but  they  extend  the  time  limit  of  the  reaction 
proportionately  to  the  degree  of  the  dilution  used. 

Cultures  from  twelve  to  twenty-four  hours  old,  grown  in 
neutral  peptone  bouillon  from  a  stock  agar- agar  culture,  are  best 
adapted  for  the  test.  It  is  advisable  to  keep  all  the  cultures  at 
room  temperature,  and  to  transplant  the  stock  agar  growths  not 
oftener  than  once  a  month,  since  cultures  "forced"  by  incubation 
and  by  frequent  transplanting  may  give  rise  to  false  reactions 
with  non-typhoid  blood.  The  cultures  should,  of  course,  be  ab- 
solutely uncontaminated,  and  must  respond  typically  to  the 
recognized  tests  for  their  identification. 

The  test  may  be  conducted  either  microscopically,  by  the  dried 
blood  method,  or  by  the  use  of  fluid  blood  or  fluid  serum;  or 
macroscopically,  the  method  preferred  by  Widal.1 

The  dried  blood  method,  perfected  and  popularized  by  Wyatt 
Johnston,2  is  to  be  chosen  whenever  it  is  necessary  to  send  the 
blood  sample  any  distance  for  examination,  and  where  the  ex- 
aminer finds  it  convenient  to  carry  with  him  to  the  patient's 
bedside  the  test-tubes  required  for  the  methods  next  to  be  de- 
scribed. Johnston's  method  is  especially  adapted  for  use  by 
health  boards,  by  which  bodies  it  is  now  extensively  employed 
in  nearly  all  the  large  cities  in  this  country. 

1  Bull,  med.,  1896,  vol.  x,  pp.  618  and  766. 

2  N.  Y.  Med.  Jour.,  1896,  vol.  l.xiv,  p.  573. 


ENTERIC  FEVER. 


399 


The  technic  of  collecting  the  blood  specimens  is  exceedingly 
simple.  After  having  punctured  the  ringer  or  ear  in  the  usual 
manner,  several  separate  drops  of  blood  are  collected  upon  the 
surface  of  some  non-absorbent  material,  preferably  glass,  then 
dried,  placed  in  an  envelop  or  other  protective  covering,  and 
tested  at  the  examiner's  convenience.  Glass  slides  or  slips  of 
non-absorbent  Bristol  board  or  paper  are  most  commonly  used 
for  collecting  the  blood  samples,  and  specimens  thus  obtained 
may  be  kept  for  several  months  without  aseptic  precautions  and 
still  retain  their  agglutinative  powers. 

If  the  specimen  has  been  collected  on  glass,  one  of  the  crusts 
is  moistened  with  a  drop  of  sterile  water  and  worked  up  into  a 
thin  paste  with  a  platinum  loop,  after  which  complete  solution 
and  proper  dilution  of  the  blood  are  effected  by  adding  twenty 
drops  of  typhoid  bouillon  and  mixing  thoroughly.  If  the  sample 
has  been  dried  on  a  paper  or  cardboard  surface,  the  blood  crust 
may  be  cut  out  with  a  pair  of  scissors  and  placed  to  soak,  face 
downward,  in  a  watch-glass  containing  twenty  drops  of  the  culture. 

From  one  of  these  mixtures  of  blood  and  typhoid  culture  a 
minute  portion  is  transferred  to  the  center  of  a  clean  cover-glass, 
which  is  at  once  inverted  over  a  "  concave  slide,"  sealed  with 
cedar  oil,  and  examined  as  a  hanging-drop  with  a  J-inch  dry 
objective,  using  dim  illumination.  A  plain  glass  slip  is  used  by 
many  workers  instead  of  a  "hollow  slide,"  but  either  will  prove 
satisfactory. 

If  the  -fluid  blood  method  is  used,  the  dilution  is  made  at  the 
patient's  bedside,  by  adding  one  drop  of  the  whole  blood  as  it 
flows  from  the  puncture  to  twenty  drops  of  typhoid  bouillon  con- 
tained in  a  small  test-tube.  The  mouth  of  the  tube  is  then  closed 
by  a  cotton  plug,  and  its  contents  are  thoroughly  mixed  by  vigorous 
snaking.  At  the  time  of  the  test,  which  must  not  be  delayed 
more  than  a  few  hours  after  the  dilution  is  made,  a  small  drop  of 
the  mixture  is  removed  from  the  tube  and  examined  microscopic- 
ally in  the  usual  manner.  In  order  to  insure  accurate  dilutions, 
a  graduated  pipette  is  needed  for  measuring  the  blood  and  the 
culture,  for  the  drops  of  both  liquids  must  be  of  exactly  the  same 
size.  Either  the  special  pipettes  devised  for  serum  testing  or  the 
Thoma-Zeiss  leucocytometer  will  prove  satisfactory  for  this  pur- 
pose. In  lieu  of  either  of  these  instruments  a  graduated  pipette 
may  readily  be  made  from  a  bit  of  glass  tubing  or  an  ordinary 
medicine  dropper. 

If  the  liquid  serum  method  is  chosen,  fifteen  or  twenty  drops  of 
blood,  drawn  by  making  a  rather  deep  puncture,  are  allowed  to 
flow  into  a  narrow- calibered  test-tube,  and  set  aside  for  a  few 


400 


GENERAL  ] ] EMATOLOGY . 


minutes  until  coagulation  has  taken  place.  As  soon  as  the  clot 
has  formed  the  nose  of  the  graduated  pipette  is  thrust  into  the 
test-tube,  and  one  drop  of  the  fluid  serum  sucked  up  and  diluted 
with  twenty  drops  of  typhoid  bouillon  contained  in  a  second  test- 
tube.  The  preparation  for  microscopical  examination  is  then 
made  from  this  dilution.  If  the  requisite  apparatus  is  at  hand, 
the  serum  may  be  obtained  by  centrifugalization. 

If  the  macroscopical  method  is  employed,  the  whole  procedure 
must  be  carried  out  under  the  strictest  aseptic  precautions,  for 
otherwise  the  growth  of  contaminating  bacteria  may  interfere  with 
the  reaction,  owing  to  the  length  of  time  required  for  the  comple- 
tion of  the  experiment. 

The  blood  from  which  the  serum  is  obtained  is  aspirated  from 
one  of  the  superficial  veins  of  the  arm,  according  to  the  technic 
employed  in  bacteriological  examinations,  and  then  immediately 
expelled  into  a  sterile  test-tube,  which  is  plugged  with  cotton  and 
set  aside  until  clotting  occurs.  If  it  is  desired  to  send  the  speci- 
men any  distance,  the  blood  may  be  drawn  up  into  a  glass  bulb, 
previously  sterilized  by  heat,  and  then  sealed  at  both  ends.  Blood 
collected  in  this  manner  will  preserve  its  agglutinative  properties 
and  remain  sterile  indefinitely. 

Having  thus  obtained  the  serum  from  the  whole  blood,  the 
test  is  carried  out  by  adding  the  serum  in  definite  dilutions  to 
either  a  twenty-four-hour-old  bouillon  culture  of  the  typhoid 
bacillus  or  to  sterile  bouillon  inoculated  with  a  typhoid  culture 
at  the  time  of  the  test. 

In  the  first  instance,  a  i  :  20  dilution  of  serum  and  twenty-four- 
hour  typhoid  bouillon  is  made  in  a  sterile  test-tube,  which  is  then 
plugged  and  placed  in  an  incubator,  where  it  remains  for  about 
twelve  hours  at  a  temperature  of  370  C.  At  the  expiration  of 
this  time  a  positive  reaction  may  be  recognized  by  the  presence 
of  dense,  whitish,  flaky  masses  (composed  of  large  clumps  of 
agglutinated  bacteria),  forming  in  the  typical  positive  reaction  a 
thick  precipitate  at  the  bottom  of  the  test-tube,  which  contrasts 
with  the  perfectly  clear  appearance  of  the  supernatant  bouillon. 
If  the  reaction  is  negative,  the  tube  shows  simply  the  uniform 
cloudiness  of  an  ordinary  typhoid  bouillon  culture. 

In  the  second  instance  a  1  :  20  dilution  of  serum  and  sterile 
neutral  peptone  bouillon  is  made,  the  mixture  then  being  inocu- 
lated with  a  small  loopful  of  typhoid  bacilli  derived  from  either  a 
bouillon  or  an  agar  culture.  The  contents  of  the  test-tube  are 
then  thoroughly  mixed,  and  the  preparation  incubated  at  370  C. 
for  twenty-four  hours.  A  positive  reaction  is  characterized  after 
this  length  of  time  by  the  formation  of  a  similar  grayish- white 


ENTERIC  FEVER. 


401 


precipitate  at  the  bottom  of  the  tube,  underlying  an  unclouded 
layer  of  fluid.  In  negative  reactions  the  typical  cloudiness  of  the 
typhoid  growth  is  diffused  throughout  the  bouillon. 

In  both  of  these  macroscopical  methods  control  tubes  of  normal 
serum  and  typhoid  bouillon  should  invariably  be  prepared,  and 
incubated  side  by  side  with  the  specimen  of  serum  to  be  tested. 

Both  tests  may  be  carried  out  at  ordinary  room  temperature, 
but  more  certain  and  more  typical  results  are  obtained  when  the 
tubes  are  incubated  at  a  temperature  of  370  C. 

The  Test  with  Dead  Cultures. — Reudiger,1  modifying  Ficker's 
technic,2  has  devised  a  very  satisfactory  serum  test  with  a  solution 
of  dead  Eberth  bacilli,  made  by  adding  1  c.c.  of  formalin  to  100  c.c. 
of  typhoid  bouillon.  Four  drops  of  the  suspected  blood  are  mixed 
with  2  c.c.  of  a  1  :  500  aqueous  solution  of  formalin,  and,  after 
laking  has  occurred,  1  c.c.  of  this  blood  solution  is  mixed  in  a 
small  test-tube  with  4  c.c.  of  the  dead  culture.  This  gives  ap- 
proximately a  30  :  1  dilution  of  the  blood.  The  test-tube  is  then 
set  aside  in  a  vertical  position,  with  the  result  that,  if  the  reaction 
is  positive,  a  flocculent  precipitate  will  appear  within  an  hour 
or  two,  falling  to  the  bottom  of  the  tube  as  a  granular  sediment,o 
with  clearing  of  the  supernatant  bouillon  within  from  twelve  to 
twenty-four  hours.  By  microscopical  examination  this  sediment 
is  found  to  consist  of  tightly  clumped  masses  of  bacilli. 

In  his  clinic  at  the  Jefferson  Hospital  the  writer  uses  this  test, 
in  connection  with  the  more  rapid  hanging-drop  method  with  live 
bacilli,  in  all  suspected  enterics,  and  regards  it  as  quite  as  accurate 
as  the  older  method,  although,  of  course,  much  slower.  Dried 
blood  as  well  as  fresh  may  be  employed,  if  the  precaution  is  taken 
to  powder  it  finely  before  adding  it  to  the  formalin  solution. 
Reudiger  obtained  positive  results  with  test  cultures  killed  a  year 
previously. 

The  Choice  of  a  Method— -The  choice  between  the  methods 
of  serum  testing  described  above  must  depend  largely  upon  the 
circumstances  under  which  the  test  is  to  be  made. 

The  dried  blood  method,  as  already  remarked,  is  best  adapted 
to  health  board  necessities,  where  samples  of  blood  are  collected 
by  the  general  practitioner  and  sent  by  mail  to  the  laboratory. 
The  chief  objection  to  this  method  is  the  impossibility  in  many 
cases  of  making  accurate  dilutions,  since  usually  it  can  only  be 
assumed  that  a  given  crust  of  blood  represents  the  same  volume 
in  its  liquid  state  as  the  drop  of  culture  with  which  it  is  diluted. 
If  the  examiner  collects  the  specimens  himself,  quite  accurate  dilu- 

1  Jour.  Infect.  Dis.,  1904,  vol.  i.  p.  236. 

2  Berlin,  klin.  Wochenschr.,  1903,  vol.  xl,  p.  102 1. 

26 


402 


GENERAL  HEMATOLOGY. 


tions  may  be  obtained  if  a  graduated  pipette  or  a  platinum  loop 
of  fixed  size  is  used  to  measure  both  the  blood  and  the  culture. 
Another  drawback  is  the  fact  that  more  or  less  typical  agglutina- 
tion occasionally  occurs  with  non-typhoid  blood,  although  John- 
ston believes  that  this  source  of  error  may  always  be  eliminated 
by  using  cultures  of  sufficient  attenuation. 

In  hospital  work  either  the  fluid  blood  or  fluid  scrum  should 
be  chosen,  for  exact  dilutions  may  be  made  by  these  methods,  and 
if  the  test  is  made  within  a  reasonable  length  of  time  after  the 
dilution,  bacterial  contamination  need  not  be  feared.  The  writer, 
a  warm  advocate  of  Johnston's  method  in  the  early  days  of  serum 
testing,  has  now  discarded  it  wherever  possible  in  favor  of  the 
more  accurate  and  equally  simple  test  performed  with  the  fluid 
whole  blood  or  serum. 

The  macroscdpical  method  with  fluid  serum  is  too  slow,  and 
requires  too  elaborate  bacteriological  apparatus  ever  to  be  adopted 
for  general  clinical  use.  Reudiger's  method  is  obviously  of 
great  value  to  the  practitioner  who  has  not  access  to  a  laboratory.1 

Value  o]  the  Serum  Test. — Fully  95  per  cent,  of  all  typhoids  give 
a  positive  reaction  at  some  period  of  the  disease,  usually  as  early 
as  the  eighth  day,  as  nearly  as  it  is  possible  to  compute  this  period. 
An  error  of  about  three  per  cent,  must  be  allowed  for,  on  account 
of  the  occurrence  of  positive  or  misleading  results  with  non-typhoid 
blood.  The  statistics  of  the  Philadelphia  Bureau  of  Health2  are 
of  interest  in  demonstrating  the  usefulness  of  the  test  in  routine 
public  health  work.  These  data,  covering  a  period  of  six  years 
(1897-1902),  show  that,  of  22,521  tests  by  the  dried  blood  method, 
in  19,080  cases  diagnosed  as  enteric  fever,  the  discrepancy  between 
the  laboratory  and  the  clinical  diagnosis  ranged  between  3.9  and 
8.3  per  cent'.  Rosenberger's  collection3  of  17,280  cases  from 
other  sources  shows  16,352  positive  results,  or  94.6  per  cent.  ^ 

In  some  instances  repeated  negative  results  are  found  until  con- 
valescence is  well  established,  and,  rarely,  cases  are  encountered 

1  A.  J.  Wolff  (Amer.  Jour.  Med.  Sci.,  1903,  vol.  exxv,  p.  661)  has  devised  a 
clever  method  of  serum  testing  with  the  patient's  blood  and  feces.  _  Bouillon 
cultures  of  the  patient's  feces  are  incubated  for  twelve  hours,  mixed,  in  definite 
dilution,  with  his  blood,  and  examined  microscopically.  If  Eberth  bacilli  exist 
in  the  culture  thus  made,  they  become  clumped  and  immobilized,  while  the  motility 
of  the  colon  organisms  also  present  is  unimpaired.  If  no  reaction  occurs,  the 
patient's  blood  should  be  tested  in  the  usual  manner  as  a  control.  _  Wolff  reports 
uniformly  positive  results  in  35  cases  of  enteric  fever  with  this  modification  of  the 
Widal  test,  and  claims  that  reactions  occur  from  the  fourth  to  the  seventh  day— 
in  spite  of  the  general  impression  that  the  stools  in  typhoid  do  not  contain  the 
Eberth  bacillus  before  the  tenth  or  eleventh  day  of  the  disease. 

2  A.  C.  Abbott,  Annual  Report  of  the  Division  of  Bacteriology,  Pathology,  and 
Disinfection  of  the  Philadelphia  Bureau  of  Health,  1903,  p.  112. 

3  Proc.  Path.  Soc.  Phila.,  1904,  vol.  vii,  p.  97. 


ENTERIC  FEVER. 


403 


in  which  the  reaction  never  occurs  at  any  time  during  the  entire 
course  of  the  illness.  The  blood  may  lose  its  clumping  powers 
at  about  the  time  of  defervescence,  or,  on  the  other  hand,  this 
peculiarity  may  persist  for  months  or  even  years  after  the  attack. 
This  last  source  of  error  in  the  test  may  be  due  to  the  presence 
of  unsuspected  foci  containing  typhoid  bacilli,  but  sometimes  it 
is  apparently  independent  of  such  factors.  Before  pronouncing 
upon  the  value  of  a  positive  reaction  in  the  individual  case  the 
occurrence  of  a  previous  attack  of  typhoid  and  the  presence  of 
lesions  which  may  be  due  to  the  Eberth  bacillus  (osteomyelitis, 
cystitis,  arthritis,  cholecystitis,  etc.)  must  be  excluded. 

The  reaction  may  be  positive  on  one  day  of  the  disease  or  for 
a  series  of  days,  and  negative  on  the  next  day  or  succeeding  days. 
Its  character  is  apparently  uninfluenced  by  the  intensity  of  the 
infection,  for  although,  as  a  rule,  the  reaction  is  usually  prompt 
and  marked  in  severe  infections,  it  may  be  just  as  marked  in  mild 
cases.  A  certain  relationship  seems  to  exist  between  the  height 
of  the  fever  and  the  intensity  of  the  reaction,  for  the  latter  is 
usually  most  decided  at  the  period  of  maximum  pyrexia. 

Positive  Reactions  in  Non-typhoid  Conditions. — In  a  number 
of  conditions  other  than  enteric  fever  the  blood  may  acquire  a 
more  or  less  decided  agglutinative  action  toward  the  Eberth 
bacillus,  but,  with  rare  exceptions,  such  reactions  are  attributable 
to  low  dilutions,  to  a  prolonged  time  limit,  and,  perhaps,  to  a 
previous  attack  of  typhoid.  Typhus  fever,  malarial  fever,  sepsis, 
pneumonia,  tuberculosis,  acute  osteomyelitis,  and  influenza  are 
among  the  most  important  diseases  thus  simulating  a  true 
typhoid  reaction,  and  a  positive  test  in  any  of  these  conditions 
must,  to  be  conclusive,  occur  in  a  high  dilution — 1  :  50,  1  :  60, 
or  higher.  In  Weil's  disease  positive  reactions  are  common,  even 
in  high  dilutions,  and  this  fact  tends  to  corroborate  Weil's  original 
suggestion,  that  this  disease  in  reality  is  nothing  more  than 
typhoid  aborted  by  the  supervention  of  jaundice.  Or,  as 
Lubowski  and  Steinberg  suggest,1  the  reaction  may  sometimes  be 
due  to  a  Bacillus  proteus  infection,  since  immune  proteus  serum 
may  agglutinate  the  Eberth  bacillus,  in  very  high  dilutions.  The 
blood  of  patients  suffering  from  other  forms  of  jaundice  also  has 
a  moderately  strong  agglutinative  effect  upon  the  typhoid  bacillus, 
although  bile  itself  has  no  such  action.  With  proper  technic, 
however,  the  blood  of  jaundice  cases  need  not  be  a  source  of 
error,  for  Libman,2  in  a  study  of  35  such  instances,  failed  to 
find  in  any  one  of  them  greater  agglutinative  effect  than  is  often 

1  Deutsch.  Arch.  f.  klin.  Med.,  1904,  vol.  lxxix..,  p  396. 

2  Med.  News,  1904,  vol.  lxxxiv,  p.  204. 


404 


GENERAL  HEMATOLOGY. 


seen  in  normal  blood.  Errors  of  technic  and  latent  or  previous 
typhoid  infection  are  the  probable  explanation  of  most  of  the 
positive  results  with  bilious  blood  and  typhoid  cultures,  reported 
by  Koenigstein,  Kochler,  Greenbaum,  and  other  earlier  students 
of  this  question. 

In  paratyphoid  fever  the  blood  serum  usually  does  not  clump 
the  Eberth  organism,  although  in  an  occasional  instance  it  does 
so,  even  in  high  dilutions.  In  doubtful  cases,  therefore,  the  ag- 
glutination reaction  with  the  typhoid  bacillus  should  always  be 
supplemented  by  similar  tests  with  paratyphoid  cultures,  as  well 
as  by  bacteriological  examination  of  the  blood  for  the  isolation 
of  a  specific  bacterium. 

In  the  light  of  our  present  knowledge  of  the  serum  test  its 
value  appears  to  be  less  than  its  first  enthusiastic  advocates  were 
inclined  to  urge.  '  A  positive  reaction,  obtained  by  a  skilled 
worker  whose  technic  as  to  dilution,  time  limit,  and  culture  has 
been  exact,  is  the  most  valuable  single  sign  of  enteric  fever,  al- 
though it  cannot  be  regarded  as  absolutely  pathognomonic.  On 
the  other  hand,  a  negative  result  with  the  test  is  no  proof  of  the 
absence  of  the  disease. 

Anemia  develops  shortly  after  the  beginning 
Hemoglobin  of  the  fever,  slowly  and  progressively  increasing 
and  in  intensity  throughout  the  course  of  the  disease, 
Erythrocytes,  and  persisting  during  the  early  weeks  of  defer- 
vescence. During  the  first  week  there  is  little  or 
no  decrease  in  the  number  of  erythrocytes,  although  the  hemo- 
globin loss  appears  to  begin  coincidentally  with  the  first  manifes- 
tations of  the  infection.  Normal  erythrocyte  counts  are  the  rule 
during  the  first  seven  days,  but  there  are  few  cases  of  typhoid 
which  fail  to  show  a  hemoglobin  loss  amounting  to  at  least  15 
or  20  per  cent,  during  this  period.  Whether  this  early  oligo- 
chromemia  is  due  to  the  influence  of  the  fever,  or  whether  it  rep- 
resents the  actual  prefebrile  state  of  the  patient's  blood,  is  difficult 
to  decide.  By  the  second  week  the  corpuscular  decrease  becomes 
evident  and  steadily  grows  more  and  more  marked  as  the  disease 
progresses,  reaching  its  maximum  at  about  the  end  of  deferves- 
cence. Thayer  1  distinguishes  a  slight  accentuation  of  the  oligo- 
cythemia between  the  third  and  fourth  weeks,  the  decrease  con- 
tinuing until  the  seventh,  when  a  still  more  decided  fall  occurs, 
followed  in  the  eighth  week  by  a  considerable  rise.  A  slow  rise 
in  the  erythrocyte  curve  is  observed  after  defervescence,  and, 
indeed,  sometimes  before  the  end  of  the  febrile  stage,  until  by  the 
end  of  the  fourth  or  fifth  week  of  convalescence  the  count  is  again 

1  Johns  Hopkins  Hosp.  Reports,  1900,  vol.  viii,  p.  487- 


ENTERIC  FEVER. 


40S 


normal.  The  hemoglobin  after  the  first  week  follows  the  same 
general  course  as  the  erythrocytes,  but  its  decrease  during  the 
early  weeks  is  relatively  greater  and  its  regeneration  slower  during 
the  post-febrile  period.  These  data,  as  well  as  those  relating  to 
the  leucocvtes,  have  been  confirmed  by  W.  A.  Winter.1 

Thayer's  analysis  2  of  the  blood  examinations  in  enteric  fever, 
made  in  the  Johns  Hopkins  Hospital  during  a  period  of  eleven 
years,  furnishes  a  striking  illustration  of  the  development  of  the 
anemia  during  the  progress  of  the  disease.  Arranged  according 
to  the  week  of  the  fever,  the  following  hemoglobin  and  ery- 
throcyte averages  in  uncomplicated  cases  are  shown: 


Hemoglobin. 
(165  estimates.) 


1  st  week,  21  estimates. . .  76.1  per  cent. 
2d     "     51        "      ...72.8  "  " 
3d     "     34       "      ...66.2  "  44 
4th    "     20        "  ...60.5 
5th    "     20       "      ---57-8  "  " 


6th  week,  6  estimates . 
7th  "4 

8th  "3 
9th    "4  " 
10th     "2  " 


62.1  per  cent, 

■5o.5  "  " 

56.9  "  " 

■47-7  "  " 

.66.5  "  44 


Erythrocytes 
(265  counts.) 
1st  week,  32  counts  4,913,312 


2d  ' 

86 

3<*  ' 

'  59 

4th  4 

36 

5th  4 

'  22 

6th  ' 

7 

4,692,428 
4,429,208 
.4,222,236 

.4,118,590 

.  4,028,428 


7th  week, 
8th  " 
9th  44 
10th  44 
nth  " 


8  counts  3,309,125 

7    "   3.652,285 


3,509,966 
3,920,000 
2,109,333 


Seventy-four  typhoid  patients,  both  with  and  without  compli- 
cations, examined  in  the  German  and  the  Jefferson  Hospitals 
showed  the  following  averages,  the  first  estimates  being  taken  in 
all  cases  in  which  multiple  examinations  were  made : 


Week.  Hemoglobin. 
1  st  week,  14  cases  77-4  per  cent. 


2d 

3d 
4th 

5th 
6th 
7th 
8th 


30 
13 
6 
6 
2 


66.5 
58.8 
49.6 

•53-i 
47-5 
•47-5 
.40.0 


Erythrocytes. 
4,789,285'per  c.mm. 
4,161,233  "  " 
3,555,ooo  "  " 

3,490,833  " 

2,445,000 

3,165,000 

3,335,000 " 
2,790,000 u  " 


As  a  rule,  the  degree  of  a  typhoid  anemia  is  parallel  to  the 
severity  of  the  attack,  but  this  is  not  invariably  true,  since  a  mild 
case  may  be  associated  with  a  most  intense  anemia.    In  the  series 

1  Dublin  Jour.  Med.  Sci.,  1901,  vol.  cxii  p.  249.  2  Loc.  cit. 


406 


GENERAL  HEMATOLOGY. 


included  in  the  last  tabulation  the  most  marked  instances  of 
anemia  showed  hemoglobin  and  erythrocyte  estimates  of  40  per 
cent,  and  1,720,000;  40  per  cent,  and  1,850,000;  and  50  per  cent, 
and  1,800,000,  respectively.  The  most  striking  example  of  oligo- 
chromemia  showed  a  hemoglobin  percentage  of  20,  with  a  cor- 
responding erythrocyte  count  of  2,470,000.  Considerably  lower 
estimates  than  these  have  been  reported  by  a  number  of  other 
observers,  but  they  are  uncommon. 

The  effects  of  the  cold  tub  and  of  excessive  diarrhea  and 
sweating  may  cause  a  temporary  polycythemia  from  concentration 
of  the  blood,  and  these  sources  of  high  counts  must  be  excluded 
in  making  examinations  during  the  early  weeks  of  the  disease. 
In  four  cases  examined  by  the  writer  to  determine  the  effects  of 
the  cold  plunge  it  was  found  that  the  average  erythrocyte  increase 
after  the  bath  amounted  to  813,000  corpuscles  per  c.mm.,  and 
the  hemoglobin  gain  to  8  per  cent.  Hemorrhages,  if  severe,  may 
cause  an  abrupt  fall  in  the  erythrocyte  count,  often  succeeded  by 
a  more  or  less  successful  attempt  at  regeneration,  in  an  effort  to 
compensate  for  the  blood  loss. 

Qualitatively,  the  cells  show  no  peculiar  changes,  poikilocytosis, 
irregular  staining  affinities,  and  deformities  of  size  occurring  in 
relation  to  the  intensity  of  the  anemia.  Erythroblasts  are  com- 
paratively rare,  being  absent  or  few  in  number  in  the  average  case. 
Normoblasts  may  be  found  in  cases  with  high-grade  anemia  and 
as  a  sequel  to  hemorrhage.  Megaloblasts  are  very  rare,  an  occa- 
sional cell  of  this  type  being  observed  now  and  then  only  in  severe 
cases. 

A  steady,  slow  decrease  in  the  number  of  leu- 
Leucocytes.  cocytes  becomes  evident  after  the  first  week  of 
the  fever,  the  lowest  counts  being  found  during 
the  fifth  or  sixth  week,  after  which  an  increase,  which  may  be 
either  permanent  or  transient  and  followed  by  a  still  more  decided 
leucopenia,  is  observed.  It  appears  that  the  latter  change  accom- 
panies cases  with  severe  post-febrile  anemia,  although  sufficient 
data  are  lacking  to  justify  absolutely  positive  conclusions  on  this 
point.  In  uncomplicated  cases  the  normal  count  becomes  re- 
established by  about  the  fourth  week  of  convalescence.  The 
leucopenia  of  typhoid  corresponds  in  a  general  way  to  the  severity 
of  the  attack,  and  although  not  marked  in  the  average,  in  the 
individual  case  it  may  be  striking,  counts  of  from  2000  to  3000 
being  not  at  all  uncommon. 

Kast  and  Gutig,1  in  105  cases,  found  the  leucocytes  below 
7000  in  97,  between  7000  and  9000  in  6,  and  9000  or  higher  in  2 

1  Deutsch.  Arch.  f.  klin.  Med.,  1904,  vol.  lxxx,  p.  104. 


ENTERIC  FEVER. 


407 


cases.  Contrary  to  the  experience  of  others  (see  below),  these 
authors  found  little  or  no  leucocytosis  as  the  effect  of  non-typhoid 
complications,  which  in  their  cases  generally  caused  simply  a 
polynuclear  increase  with  no  disturbance  of  the  leucopema. 

Thayer's  report  of  832  counts  in  uncomplicated  cases  shows 
the  following  range  of  the  leucocytes,  according  to  the  week  of 
the  disease: 


1st  week,  119  counts 
2d 

3d 
4th 
5th 
6th 
7th 


258 
200 
117 
70 
25 
14 


. . . 6442 
-  - -6251 
-•-5528 
- --5431 
---5510 
...5690 
...6132 


8th  week,  14  counts. . 

. .6614 

9th  " 

7     "  -- 

--5057 

10th  " 

2  " 

..5000 

nth  " 

3     "  -- 

--5333 

12th  " 

2  " 

-  -  5°°° 

13th  " 

1  " 

. .8000 

The  leucocyte  estimates  of  the  74  hospital  typhoids  referred  to 
above  averaged: 


Tst  week,  14  cases 


2d  ' 

3° 

3d  ' 

13 

4th  ' 

6 

5*  < 

6 

6th  ' 

7th  ' 

2 

Sth  ' 

1 

.8026  leucocytes  per  c.mm. 
6713 

7076  " 

.4400  " 

•5766  11     ;;  ;; 

6250  "  u  « 

.4500 

.8000  " 


Disregarding  the  week  of  the  fever,  the  number  of  leucocytes 
in  these  cases  ranged  as  follows: 


7  ( 

3 
8 

14 
8 
.  10 
.  11 

.  8 

4 
.  1 


Above  10,000  in  

From    9,000-10,000  in  

8,000—  9,000  "   

7,000-  8,000  "   

6,000-  7,000  "   

5,000-  6,000  "   

4,000—  5,000  "   

3,000-  4,000  "   

2,000—  3,000  "   

1,000—  2,000  "   

Highest,  16,000  per  c.mm. 
Lowest,    1,333  " 
Average,  6,706    "  " 

It  appears  from  these  figures  that  counts  in  excess  of  10,000 
per  c.mm.  may  be  looked  for  in  more  than  ten  per  centfof  all 
cases,  such  an  increase  being  due  either  to  the  effects  of  blood 
concentration  from  diarrhea,  sweating,  vomiting,  or  cold  tubbing, 
or  to  some  hidden  or  frank  complication.  In  four  of  the  seven 
relatively  high  counts  above  noted  the  cause  was  plain— croupous 
pneumonia  in  two,  cholecystitis  in  one,  and  furunculosis  in  one. 


408 


GENERAL  HEMATOLOGY. 


In  the  other  three,  all  of  which  were  made  in  patients  whose  fever 
had  not  yet  run  seven  days,  the  factors  of  the  increase  were  unde- 
termined; possibly  it  was  due  to  physiological  blood  inspissation. 

Inflammatory  complications,  such  as  otitis,  abscess,  pneumonia, 
severe  bronchitis,  peritonitis,  cystitis,  periostitis,  and  phlebitis,  give 
rise  to  a  prompt  leucocytosis  in  patients  whose  vital  powers  are 
sufficiently  strong  to  react  against  the  process.  Intestinal  hemor- 
rhage is  usually  followed  by  an  increase  reaching  its  maximum 
within  twenty-four  hours  after  the  blood  loss,  and  disappearing 
within  a  week.  Intestinal  perforation  may  promptly  be  followed 
by  a  leucocytosis,  the  increase  developing  within  a  few  hours. 
Thayer  has  observed  that  in  some  instances  the  increase  in  the 
number  of  leucocytes  succeeding  the  perforation  may  tend  to 
diminish  and  disappear  with  the  aggravation  of  the  symptoms, 
and  that  not  infrequently  there  is  a  complete  absence  of  leucocy- 
tosis and  sometimes  a  diminution  in  the  number  of  leucocytes 
after  this  accident.  He  also  considers  that  the  prospect  of  relief 
by  surgical  interference  is  best  in  those  cases  with  a  leucocytosis, 
the  absence  or  disappearance  of  this  sign  following  a  perforation 
being  an  indication  of  the  malignancy  of  the  infection  or  the  pros- 
tration of  the  patient. 

Qualitative  changes  are  absent  or  inconspicuous  during  the 
first  two  weeks  of  the  fever,  but  during  the  third  week  a  slow, 
progressive  decrease  in  the  relative  percentage  of  polynuclear 
neutrophiles  with  a  consequent  increase  in  the  mononuclear  un- 
granulated  forms,  begins,  this  change  becoming  most  marked  at 
about  the  end  of  defervescence.  In  23  of  the  writer's  cases  the 
percentage  of  polynuclears  averaged,  according  to  the  week  of 
the  disease,  75.0  per  cent,  for  8  cases  in  the  first  week;  70.9  per 
cent,  for  7  in  the  second  week;  50.2  for  4  in  the  third  week;  60.0 
per  cent,  for  2  in  the  fourth  week;  and  64.0  and  68.0  per  cent, 
for  a  single  case  in  the  fifth  and  sixth  weeks,  respectively.  Higley 1 
finds  that  the  polynuclear  neutrophiles  decrease  much  earlier  in 
the  disease,  9  of  his  cases  examined  during  the  first  week  showing 
an  average  of  59.4  per  cent,  for  these  cells. 

Thayer  has  found  that  the  mononuclear  cells  which  are  most 
markedly  increased  are  "  elements  containing  nuclei  not  much 
larger  than  those  of  lymphocytes,  and  often  presenting  the  general 
appearance  of  a  lymphocyte  nucleus,  with  the  exception  of  the 
slight  affinity  for  coloring  matters.  The  size  of  these  cells  is 
usually  about  that,  or  but  little  larger  than  that,  of  the  ordinary 
polymorphonuclear  neutrophile."  The  typical  small  lymphocyte 
and  the  transitional  forms  undergo  little  or  no  increase. 

1  Med.  News,  1903,  vol.  lxxxiii,  p.  1140. 


ENTERIC  FEVER. 


The  eosinophiles  arc  almost  invariably  decreased,  both  abso- 
lutely and  relatively,  and  arc  often  absent  during  the  active 
febrile  stages.  The  relative  percentages  of  these  cells  in  the 
above  cases  averaged  0.87,  rising  as  high  as  5  per  cent,  in  only 
2  cases,  and  being  entirely  absent  inn. 

Myelocytes  in  small  numbers  may  be  found  in  severe  forms 
of  post-typhoid  anemia,  but  they  are  absent  during  the  active 
period  of  the  infection.  Turk's  "stimulation  forms"  are  met 
with  under  the  same  conditions. 

Thayer's  elaborate  report  of  the  Johns  Hopkins  Hospital  cases 
includes  the  following  averages  of  the  differential  leucocyte  counts : 


Week. 

Small  Mono- 
nuclear. 

Large  Mono- 
nuclear. 

Polynuclear 
Neutrophile. 

EOSINOPHILE. 

1st  week,  12  counts 
2d     "     39  " 

3d      "     34  " 
4th    "     19  " 
5th    "      8  " 
6th    "      4  " 
7th    "      1  " 
8th    "      1  " 

12.9  per  cent. 
14.6  "  " 

21.5  "  " 

20.1  "  " 

18.2  "  " 

22.6  " 

*3-7  "  " 
24.2  "  " 

12.4  per  cent. 
13-4  " 

11.6  "  " 
14.4  " 

19.7  "  " 
i3-5  "  " 
34-4  " 

16.8  "  " 
1 

74.0  per  cent. 
70.9  "  " 
66.3  "  " 
65.0  "  " 
61.7  "  " 
57-7  "  " 
37-3  "  " 
56.9  ".  " 

0.5  per  cent. 
0.8  "  " 

0.3  "  A 
0.4  "  " 
0.3  "  " 

6.0  "  " 
4.6  "  " 

2.1  "  " 

According  to  Hayem,1  the  number  of  blood  plaques  is  markedly 
decreased  during  the  febrile  period  "of  the  fever,  as  in  any  other 
condition  characterized  by  pyrexia. 

The  blood  examination  furnishes  four  clinical 
Diagnosis,  signs  of  positive  value  in  the  diagnosis  of  enteric 
fever:  the  serum  reaction;  a  subnormal  leuco- 
cyte count  or  at  least  an  absence  of  leucocytosis ;  bacteriemia; 
and  in  cases  with  roseola  the  detection  of  the  Eberth  bacillus  by 
spot  culturing.  The  influence  of  complications  upon  the  behavior 
of  the  leucocytes  must,  however,  always  be  borne  in  mind. 

Acute  miliary  tuberculosis,  cerebrospinal  meningitis,  malarial 
fever,  certain  atypical  cases  of  pneumonia  and  influenza,  and 
septicemic  and  pyemic  processes,  such  as  ulcerative  endocarditis, 
are  the  diseases  most  frequently  confounded  with  typhoid,  and  in 
their  differentiation  the  blood  report  often  gives  just  the  essential 
clue. 

Acute  miliary  tuberculosis,  if  a  pure  infection,  shows  a  similar 
absence  of  a  leucocyte  increase,  and  in  excluding  this  disease 
reliance  must  be  placed  on  the  Widal  test  and  upon  blood  cul- 
turing. Influenza  is  not  characterized  by  leucocytosis,  and  must 
be  differentiated  from  typhoid  by  the  aid  of  the  same  methods  of 

1  "Du  Sang,"  etc.  Paris,  1889. 


GENERAL  HEMATOLOGY. 


examination.  Cerebrospinal  meningitis,  pneumonia,  and  septic 
and  pyemic  conditions  may  be  differentiated  by  their  association 
with  a  more  or  less  well-marked  leucocytosis.  In  the  last-named 
processes  bacteriological  examination  of  the  blood  not  infrequently 
gives  conclusive  results.  Paratyphoid  jever,  often  clinically  identi- 
cal with  genuine  enteric  fever,  shows  also  a  similar  anemia  and 
leucocyte  range.  As  a  rule,  paratyphoid  blood  does  not  agglutin- 
ate cultures  of  the  Eberth  bacillus;  if  it  does  so.,  the  reaction  is 
less  marked  than  with  cultures  of  the  paratyphoid  organism. 
Blood  culturing  is  the  court  of  final  appeal  in  distinguishing  these 
two  closely  related  infections.  The  differentiation  of  malarial 
jever  is  referred  to  under  this  disease.    (See  p.  472.) 

;    XXII.  ERYSIPELAS. 

In  severe  infections  Turk1  has  noted  a  de- 
General     cided  increase  in  the  quantity  of  fibrin  and  in  the 
Features,     number  of  blood  plaques,  but  in  the  case  of  average 
severity  these  changes  are  not  to  be  observed. 
Drouin2  has  found  that  the  alkalinity  of  the  blood  is  greatly  de- 
creased.   Negative  results  from  bacteriological  examination  of  the 
blood  are  the  rule,  although  streptococci  (Fehleisen),  diplococci 
(Pfahler),  and  other  pyogenic  bacteria  invade  the  blood  at  and 
near  the  erysipelatous  lesions. 

Moderate  anemia,  characterized  by  a  some- 
Hemoglobin  what  disproportionate  hemoglobin  loss,  is  com- 
and         mon  in  the  severer  forms  of  the  disease,  but  not 
Erythrocytes,  in  mild  cases.    The  decreases  are  not  notable, 
amounting  on  the  average  to  a  loss  of  not  more 
than  10  or  20  per  cent,  of  corpuscles  and  of  about  30  per  cent, 
of  hemoglobin.    Maragliano's  degenerative  changes  of  corpus- 
cular structure  have  occasionally  been  found. 

Leucocytosis  of  the  polynuclear  neutrophile 
Leucocytes,  type  is  the  usual  finding,  but  mild  cases  fre- 
quently run  their  course  without  provoking  the 
slightest  increase.  Except  in  isolated  instances,  the  leucocytosis 
is  not  high,  the  counts  usually  being  about  15,000,  and  rarely 
more  than  20,000,  cells  to  the  c.mm.  Von  Limbeck 3  and  Chante- 
messe  and  Rey4  have  shown  that  the  leucocyte  and  temperature 
curves  maintain  a  definite  parallelism  in  the  majority  of  cases, 
and  that  the  diminution  in  the  leucocytosis,  as  a  rule,  anticipates 
the  fall  in  temperature.    There  is,  however,  no  apparent  rela- 

1  Loc.  tit.  2  These  de  Paris,  1892,  No.  83,  p.  108. 

3  Loc.  tit.  4  Presse  raed.,  1899,  vol.  vi,  p.  316. 


FEVER. 


411 


tionship  between  the  height  of  the  count  and  the  degree  of 
pyrexia,  for  moderate  leucocytoses  arc  not  incompatible  with 
strikingly  high  temperatures.  It  is  generally  agreed  that  the 
highest  counts  are  found  in  the  severest  cases,  provided  that  the 
patient's  resisting  powers  are  acting  normally.  An  extension 
of  the  lesion  is  generally  accompanied  by  an  increase  in  the 
leucocytosis. 

With  the  onset  of  convalescence,  as  the  leucocytosis  disappears, 
the  normal  percentages  of  the  different  forms  of  corpuscles,  dis- 
turbed during  the  febrile  period,  are  reestablished  by  a  rapid 
increase  in  the  small  lymphocytes  and  eosinophiles,  and  a  decrease 
in  the  polynuclear  neutrophiles ;  the  percentage  of  large  lympho- 
cytes remains  stationary,  and  the  eosinophiles  are  absent  during 
the  height  of  the  attack,  according  to  Chantemesse  and  Rey. 
Small  percentages  of  myelocytes  and  an  occasional  "  stimulation 
form"  are  commonly  found  during  the  active  stages  of  the  leuco- 
cytosis. 

XXIII.  EXOPHTHALMIC  GOITER. 

There  are  no  characteristic  changes  in  the  hemoglobin  and 
erythrocytes,  although  an  anemia  indistinguishable  from  typical 
chlorosis  is  not  an  infrequent  feature.  Such  cases  must  be  dis- 
tinguished from  so-called  "thyroid  chlorosis,"  or  chlorosis  with 
thyroid  hypertrophy,  by  means  of  other  clinical  symptoms.  In 
nine  cases  of  which  the  writer  has  notes  the  hemoglobin  averaged 
78.6  per  cent.,  and  the  erythrocytes  4,715,571  per  c.mm.  It 
seems  likely  that  in  cases  of  Graves'  disease  characterized  by 
excessive  diaphoresis,  emesis,  and  diarrhea,  the  blood  concen- 
tration thus  produced  may  be  sufficient  more  or  less  effectually 
to  obscure  the  real  grade  of  anemia  existing. 

The  leucocytes  are  not  increased  in  number,  and  leucopenia  of 
a  decided  degree  is  frequently  observed.  Of  the  above  cases,  the 
leucocyte  average  was  4698  per  c.mm.,  none  of  the  counts  exceeding 
10,000.  Relative  lymphocytosis  is  a  common  change,  and  moderate 
increase  in  the  percentage  of  eosinophiles  an  occasional  rinding. 


XXIV.  FEVER. 

It  is  a  well-recognized  fact  that  more  or  less  hemoglobin  and 
erythrocyte  losses  follow  pyrexia  maintained  for  any  length  of 
time,  but  an  attempt  to  demonstrate  the  exact  cause  or  group  of 
causes  of  this  anemia  involves  the  analysis  of  a  most  complex 
problem  in  physiology,  about  which  the  most  skilled  investigators 


412 


GENERAL  HEMATOLOGY. 


express  diametrically  opposite  opinions.  Some  maintain  that  suffi- 
cient actual  destruction  of  the  corpuscles  occurs  as  the  result  of 
fever  to  account  for  their  decrease  in  number,  while  others  attrib- 
ute the  loss  largely,  if  not  wholly,  to  the  influence  of  vasomotor 
changes.  Maragliano1  has  shown  that  capillary  contraction  ac- 
companies the  period  of  active  pyrexia,  while  Reinert2  suggests 
that  the  blood  is  diminished  in  volume  by  the  excessive  drain 
upon  the  body  fluids  occurring  at  this  time.  In  septic  fevers, 
furthermore,  additional  inspissation  of  the  blood  is  produced  by 
the  influence  of  bacteria  and  their  products.  These  factors,  tend- 
ing to  inspissate  the  blood,  favor  the  production  of  polycythemia, 
which  change  is  to  be  observed  during  the  stage  of  active  fever. 
But  as  defervescence  sets  in  the  conditions  are  reversed,  for  the 
capillaries  then  dilate,  the  draining  away  of  the  fluid  elements  of 
the  blood  ceases,  and,  consequently,  dilution  of  the  blood  now 
occurs.  Anemia,  therefore,  develops  coincidentally  with  the  dis- 
appearance of  the  fever.  It  is  undetermined  whether  this  post- 
febrile anemia  is  the  result  purely  of  these  physical  causes  or  of 
these  causes  plus  a  certain  amount  of  real  hematocytolysis  due 
to  high  temperature.  It  seems  reasonable  to  regard  both  factors 
as  active. 

Coagulation  and  fibrin  behave  so  erratically  that  no  definite 
statements  regarding  them  are  justified.  In  the  incipient  stage 
of  septic  fevers  coagulation  is  much  delayed,  according  to  Schmidt,3 
but  during  the  later  stage  it  occurs  more  rapidly  than  normal. 
The  leucocytes  in  this  class  of  fevers  are  generally  increased  in 
number. 

The  alkalinity  of  the  blood  undergoes  wide  variations  in  differ- 
ent febrile  states,  but  it  cannot  be  said  that  these  changes,  which 
are  probably  due  to  complex  chemical  processes  rather  than  to 
the  primary  effect  of  the  fever,  are  constantly  parallel,  either  to 
the  degree  of  pyrexia  or  to  the  behavior  of  the  leucocytes.  Lowy 
and  Richter4  state  that  increased  alkalinity  occurs  coincidentally 
with  the  stage  of  hypoleucocytosis — a  statement  which  Strauss,5 
Lowit,6  and  others  have  verified.  Fodor  and  Rigler's  experi- 
ments7 have  proved  that  the  pyrexia  following  infection  with 
pathogenic  bacteria  ultimately  effects  a  diminution  in  the  alkalinity 
of  the  blood,  and  that  this  change  is  sometimes  preceded  by  a  dis- 

1  Berlin,  klin.  Wochenschr.,  1887,  vol.  xxiv,  p.  797. 

2  "Die  Zahlung  der  rothen  Blutkorperchen,"  Leipsic,  1891. 

3  Pfliiger's  Arch.,  1875,  vol.  xi,  pp.  291  and  515. 

4  Deutsch.  med.  Wochenschr.,  1895,  vol.  xxi,  p.  526. 

5  Zeitschr.  f.  klin.  Med.,  1896,  vol.  xxx,  p.  315. 

6  "Die  Lehre  v.  Fieber,"  Jena,  1897. 

7  Centralbl.  f.  Bakt.  u.  Parasit,  1897,  vol.  xxi,  p.  134. 


TILARIASIS. 


413 


linct  primary  increase.  The  conclusions  voiced  by  von  Jaksch,1 
Krause,2  and  other  earlier  writers,  that  decreased  alkalinity  is  a 
constant  accompaniment  of  febrile  processes,  cannot  be  unreserv- 
edly accepted,  if  von  Limbeck's3  later  statements  to  the  contrary 
are  to  be  believed. 

XXV.  FILARIASIS. 

Filariasis,  the  pathological  condition  depend- 
Occurrence,  ing  upon  the  presence  in  the  body  of  the  parental 

and  embryonic  forms  of  the  Filaria  sanguinis  , 
hominis,  is  of  wide-spread  distribution  throughout  the  tropics  and 
subtropics,  being  prevalent  in  various  districts  of  Africa,  India, 
Australia,  China,  Japan,  South  America,  and  the  islands  of  the 
South  Pacific  and  the  West  Indies,  and,  as  mentioned  below,  hav- 
ing been  found  to  a  limited  extent  in  North  America. 

Six  distinct  species  of  embryo  blood  worms, 
Parasitology,  the  parental  forms  of  which  do  not  enter  the  cir- 
culation, have  been  demonstrated  in  the  periph- 
eral blood  of  man,  these  parasites  being  known  by  the  general 
term  Filaria  sanguinis  hominis.  These  different  filariae,  according 
to  the  nomenclature  suggested  by  Manson,4  are  distinguished  by 
the  names  Filaria  nocturna,5  Filaria  diurna,  Filaria  perstans,  Fila- 
ria demarquaii,  Filaria  ozzardi,  and  Filaria  magalhaesi.  To  but  a 
single  member  of  this  group,  the  Filaria  nocturna,  has  an  undis- 
puted pathological  role  been  assigned,  this  parasite  being  regarded 
as  the  cause  of  various  forms  of  ulcer,  lymphangitis,  lymph  varices, 
lymph  scrotum,  tropical  elephantiasis  Arabum,  endemic  chyluria, 
chylous  ascites,  and  other  tropical  diseases  of  more  or  less  obscure 
nature.  The  Filaria  perstans,  Manson  conjectures,  may  possibly 
be  the  cause  of  that  peculiar  tropical  disease  known  as  African 
kra-kra,  or  "  craw-craw."  Christy 6  couples  this  worm  etiologically 
with  the  "tick  fever"  of  Uganda,  and  has  shown  that  a  variety 
of  tick  (known  locally  as  the  Bibo)  acts  as  its  intermediary  host. 
Bastian7  suggests  that  the  embryonic  forms  of  the  Filaria  perstans 
are  in  reality  embryos  of  a  species  of  Tylenchus,  which  infests  the 
roots  of  the  banana.    By  eating  the  fruit  thus  contaminated  it  is 

1  Zeitschr.  f.  klin.  Med.,  1887,  vol.  xiii,  p.  380. 

2  Zeitschr.  f.  Heilk.,  1889,  vol.  x,  p.  106. 

3  Centralbl.  f.  inn.  Med.,  1895,  vol.  xvi,  p.  649. 

4  "Tropical  Diseases,"  3d  ed.,  New  York,  1903. 

5  The  author  is  greatly  indebted  to  Dr.  F.  P.  Henry  and  to  Dr.  J.  H.  Gibbon 
for  the  opportunity  of  making  repeated  blood  examinations  in  two  cases  of  Filaria 
nocturna  infection  occurring  in  their  respective  hospital  services. 

6  Thompson  Yates  and  Johnston  Lab.  Rep.,  1903,  vol.  v,  p.  187. 

7  Lancet,  1904,  vol.  i,  p.  286. 


414 


GENERAL  HEMATOLOGY. 


possible  that  some  of  the  worms  ingested  may  bore  through  the 
gut  and  reach  the  mesentery,  where  they  rest  and  develop,  and 
whence  they  later  pass  into  the  general  circulation  via  the  lymph 
stream.  Low,1  on  the  contrary,  has  pointed  out  that  the  distribu- 
tion of  the  Filaria  perstans  does  not  always  correspond  to  that 
of  ^banana  cultivation,  and  contends  that  this  organism  is  in  no 
way  related  to  the  genus  Tylenchus.  This  investigator2  has  dis- 
proved the  belief,  once  held,  that  the  Filaria  perstans  is  the 
specific  cause  of  "sleeping  sickness."  The  other  nlariae  (diurna, 
demarquaii,  ozzardi,  and  magalhaesi)  possess  no  interest  from 

a  diagnostic  standpoint, 
since  their  life  history  and 
pathological  significance 
are  still  obscure.3 

This 

The  Filaria  is  by  far 
Nocturna.  the  most 
import- 
ant member  of  the  above- 
named  class  of  blood 
worms,  being  the  one- 
most  familiarly  known 
of  all,  as  well  as  the  one 
of  greatest  clinical  in- 
terest, because  of  the 
interesting  pathological 
lesions  which  it  is  cap- 
able of  exciting.  In  this 
country  cases  of  filariasis 
due  to  the  Filaria  noc- 
turna have  been  reported  by  a  number  of  different  observers,  Gui- 
teras,4  de  Saussure,5  Mastin,6  Slaughter,7  F.  P.  Henry,8  Dunn,9  and 
Lothrop  and  Pratt 10  having  met  with  the  disease.  A  few  of  these 
cases  have  been  regarded  by  their  reporters  as  indigenous,  but  the 
great  majority  of  them,  it  is  safe  to  state,  were  directly  imported 
from  the  tropics.  To  the  writer's  knowledge,  at  least  five  cases 
have  been  diagnosed  in  Philadelphia  during  the  last  six  years. 

1  Lancet,  1904,  vol.  i,  p.  420.  2  Brit.  Med.  Jour.,  1903,  vol.  i,  p.  722. 

3  For  a  complete  description  of  filariasis  and  of  the  various  forms  of  the  filariae 
the  reader  should  consult  Manson's  text-book,  above  mentioned.  Davidson's 
"Hygiene  and  Diseases  of  Warm  Climates"  (Edinburgh,  1893)  contains  an  excellent 
account  of  the  histological  structure  of  filarial. 

4  Med.  News,  1886,  vol.  xlvii,  p.  399.  5  Ibid.,  1890,  vol.  lvi,  p.  704. 

6  Annals  of  Surg.,  1888,  vol.  viii,  p.  321.  7  Med.  News,  1891,  vol.  ii,  p.  649. 
8  Ibid.,  1896,  vol.  xviii,  p.  477.  9  Trans.  Coll.  Phys.  Phila.,  1898,  p.  80. 

10  Amer.  Jour.  Med.  Sci.,  1900,  vol.  exx,  p.  525. 


Fig.  59. — The  Filaria  Nocturna. 
From  a  photomicrograph  of  the  parasite  in  a  fresh  blood 
film. 


PILARIASIS. 


415 


As  may  be  inferred  from  the  name,  the  embryos  of  the  Filaria 
nocturna  are  found  in  the  peripheral  blood  most  abundantly  at 
night,  the  vast  majority  of  the  parasites  retiring  into  the  deeper 
circulation  during  the  daytime.  From  late  in  the  afternoon  until 
about  midnight  they  make  their  way  into  the  peripheral  vessels 
in  progressively  increasing  numbers,  with  more  or  less  fluctuation, 
the  maximum  number  being  found  at  the  latter  time,  after  which 
they  begin  to  grow  less  and  less  numerous,  until,  by  about  eight 
o'clock  in  the  morning,  they  have  practically  all  disappeared 
from  the  superficial  circulation  and  reentered  the  deeper  vessels, 
in  which  they  remain  until  the  close  of  the  day.  This  peculiar 
periodicity  is  well  illustrated  by  a  recent  series  of  investigations 
made  by  Lothrop  and  Pratt,1  who  have  charted  the  phenomenon 
in  one  case,  showing  the  approximate  number  of  parasites  to  the 
c.mm.  of  blood  as  follows:  4  p.  m.,  100;  6  p.  m.,  275;  8  p.  m.,  1300; 

IO  P.  M.,  900;  12  M.,  1500;  2  A.  M.,  700;  4  A.  M.,  900;  6  A.  M.,  125; 

8  A.  M.,  125;  and  10  A.  M.,  100.  The  highest  number  ever  ob- 
served by  these  authors  was  2100  embryos  per  c.mm.,  the  specimen 
in  which  this  count  was  made  having  been  taken  at  midnight. 
This  characteristic  periodicity,  it  should  also  be  remarked,  is  com- 
pletely reversed  if  the  individual  harboring  the  parasite  reverses 
his  habits  of  life,  sleeping  during  the  day  and  moving. about  at 
night.  If  such  should  be  the  case,  the  worms  will  appear  in  the 
peripheral  blood  during  the  daytime,  the  patient's  period  of  rest, 
and  seek  the  deeper  circulation  at  night,  the  patient's  period 
of  activity. 

The  painstaking  studies  of  Manson2  and  Low 3  have  shown  that 
mosquitos  {Culex  jatigans  and  several  of  the  genus  A  nopheles)  are 
the  intermediate  hosts  of  this  parasite,  which  may  be  found  alive 
in  the  stomachs  of  these  insects  after  they  have  fed  upon  a  filarious 
individual.  Ecdysis  takes  place  in  this  organ,  and  the  embryos, 
after  having  cast  their  sheaths,  manage  eventually  to  penetrate  the 
thoracic  muscles  of  their  host,  in  which  situation  they  undergo  a 
developmental  phase.  This  lasts  about  eighteen  days,  after  which 
the  larvas  thus  evolved  escape  from  the  thorax  and  ultimately 
reach  the  insect's  labium  and  proboscis,  whence  they  are  directly 
introduced  in  the  blood  of  man  by  the  bite  of  the  infected  mosquito. 
The  parasites  having  been  inoculated  into  a  human  being  in  this 
manner,  make  their  way  to  some  part  of  the  lymphatic  system,  in 
which  they  lodge,  sexually  mature,  fecundate,  and  beget  the 
innumerable  embryo  forms  which,  via  the  lymph  stream,  find 
their  way  into  the  circulating  blood. 

A ppearance  in  Fresh  Blood. — In  the  unstained  blood  film  the 

1  Loc.  cit.  2  Loc.  cit.  3  Brit.  Med.  Jour.,  1902,  vol.  i,  p.  1472. 


416 


GENERAL  HEMATOLOGY. 


parasite  appears  under  the  microscope  as  a  long,  slender,  graceful 
worm  possessing  a  most  remarkable  degree  of  activity.  It  measures 
about  -gV  of  an  inch  in  length  and  -g-^-Q-  °f  an  mcn  m  diameter, 
and  is  of  a  pearly-gray  color,  with  perhaps  the  faintest  suggestion 
of  a  yellowish  tone  in  certain  lights.  Its  general  appearance 
conveys  to  one,  at  first  glance,  the  impression  of  a  thin,  transparent 
tube,  through  which  a  rapidly  flowing  stream  of  liquid  is  con- 
stantly circulating.  The  head  (cephalic  end)  is  gracefully  rounded, 
while  the  tail  (caudal  end)  gradually  tapers  for  about  one-sixth 
the  entire  length  of  the  animal,  and  ends  in  a  fine-pointed  ex- 


showibo(5eofI1Se gpSS  £ fSSod  f£fm!he   pared  slide,  but  after  the  speci- 


hours,  coarse  granulations  begin  to  stipple  its  surface,  first  develop- 
ing in  the  center  and  gradually  spreading  toward  the  periphery. 
(See  Fig.  60.)  A  series  of  fine  striations,  like  the  milling  on  a 
coin,  may  be  observed  running  along  both  edges  of  the  body  at 
right  angles  to  its  long  axis.  A  viscus,  appearing  as  a  mass  of 
granular  material,  occupies  a  part  of  the  central  third  of  the  worm's 
body,  running  parallel  to  its  long  axis.  Upon  careful  examination 
with  an  oil-immersion  objective  rhythmical  dimpling  or  puckering 
movements  may  generally  be  observed  at  the  tip  of  the  cephalic 
end  of  the  embryo;  these  movements,  which  occur  with  more  or 
less  regularity  at  the  rate  of  from  twenty-five  to  forty  times  a 
minute,  have  been  attributed  to  the  act  of  respiration.    As  the 


Fig.  60. — Filaria  Nocturna. 


i) 


tremity.  The  worm  is  cylin- 
drical in  shape,  of  regular  out- 
line, and  consists  of  a  central 
body  enveloped  in  a  distinct, 
loosely  fitting,  hyaline,  struc- 
tureless sheath,  which  is  about 
as  much  too  large  for  the  body 
as  the  thumb  of  an  adult's 
glove  would  be  for  the  little 
finger  of  a  child.  Thus,  that 
part  of  the  sheath  temporarily 
unoccupied  by  the  body  is 
prone  to  collapse,  folding  upon 
itself  and  trailing  after  the 
worm  at  either  or  both  ex- 
tremities as  a  twisted,  whip- 
like ribbon.  The  greater  part 
of  the  body  appears  to  be  of  a 
homogeneous  structure  when 
examined  in  the  freshly  pre- 


men  has  been  kept  for  several 


FILARIASIS. 


417 


wriggling  of  the  worm  becomes  less  active  close  observation  will 
show  that  these  pouting  movements  are  caused  by  the  alternate 
covering  and  uncovering  of  the  cephalic  end  by  a  delicate,  six- 
lipped  prepuce.  The  sudden  projection  and  the  equally  rapid 
retraction  of  a  filamentous  fang  or  tongue-like  organ  from  the 
worm's  uncovered  head  may  also  be  noted  in  some  instances,  but 
this  characteristic  is  so  difficult  to  make  out  that  it  may  usually 
be  looked  for  in  vain.  At  a  point  about  one-fifth  of  the  entire 
length  of  the  worm  posterior  to  the  head  it  is  possible  to  make 
out  a  triangular,  slightly  luminous  patch,  shaped  like  the  letter  V, 
this  spot  being  known  as  the  V-shaped  patch,  regarded  by  Man- 
son  as  a  rudimentary  generative  organ.  A  second  spot,  some- 
what similar  to  it  in  appearance  but  smaller  in  size,  may  occasion- 
ally be  seen  at  a  point  just  above  the  tail  of  the  parasite;  this 
spot  Manson  is  inclined  to  regard  as  the  rudimentary  anus. 

The  movements  of  the  worm  are  rapid  and  violent  in  the  ex- 
treme; so  much  that  they  are  followed  with  difficulty  with  any 
but  a  low-power  dry  objective.  The  parasite  is  never  at  rest: 
one  moment  it  may  be  curled  up  into  a  tight  bunch,  like  a  coil 
of  rope;  the  next  moment  it  may  suddenly  straighten  out  and 
become  rigid  for  an  instant,  only  to  resume  its  incessant  con- 
tortions and  twistings,  which  throw  it  into  every  conceivable 
shape.  If  particular  attention  is  paid  to  the  point,  it  will  be 
noticed  that,  however  rapid  and  complicated  may  be  its  move- 
ments, the  parasite  is  never  seen  to  turn  completely  over  laterally. 
The  accompanying  series  of  sketches  of  the  Filaria  nocturna  in 
a  fresh  blood  slide  illustrate  a  few  of  the  different  forms  which 
this  parasite  may  assume  (Fig.  61).  The  worm  seems  to  move 
about  among  the  blood  corpuscles  with  graceful  and  quick  un- 
dulations of  its  body  and  abrupt  whip-like  strokes  of  its  tail, 
butting  its  head  against  the  more  resisting  masses  of  cells  or  else 
seeking  a  less  difficult  passage  around  them,  always  in  motion, 
but  never,  it  appears,  with  any  definite  aim  to  its  exertions.  Con- 
trary to  the  views  expressed  by  most  observers,  that  the  movements 
of  the  Filaria  nocturna  are  not  truly  propulsive  in  character,  the 
writer  has  repeatedly  noticed  that  "this  worm  sometimes  travels 
several  times  the  distance  of  the  diameter  of  the  microscope  field 
(J-inch  objective,  one-inch  ocular,  and  160  mm.  tube-length), 
although  in  most  cases  its  excursions  were  limited  to  a  measured 
area  not  exceeding  half  a  dozen  square  microns.  It  cannot  be  denied 
that  these  apparently  progressive  movements  of  the  worm  may  pos- 
sibly be  due  to  the  currents  in  the  blood  plasma,  but  they  certainly 
seem  to  have  every  characteristic  of  a  true  locomotive  force. 
After  the  slide  has  been  kept  for  a  few  hours,  the  movements 
27 


4i8 


GENERAL  HEMATOLOGY. 


of  the  worm,  at  first  so  confusingly  rapid,  gradually  become 
slower  and  slower,  and  these  torpid,  more  deliberate  turnings  and 
twistings  may  be  accurately  followed  under  an  immersion-lens. 
If  the  parasite  happens  to  become  confined  in  a  little  pool  of 
plasma  surrounded  by  rouleaux  of  half-dried  erythrocytes,  an 
accident  which  often  happens  when  the  drying  of  the  film  has 
spread  inward  some  little  distance  from  the  edges  of  the  cover- 
glass,  its  finer  structure  and  characteristics  may  be  studied  with 
great  ease  and  accuracy. 


Fig.  6i. — Showing  the  Changes  in  the  Shape  of  the  Filaria  Nocturna  During  the 
Period  of  Half  an  Hour. 
The  sketches,  made  at  two-minute  intervals,  all  represent  the  same  parasite. 


The  phenomenon  of  ecdysis,  or  shedding  of  the  worm's  sheath, 
with  the  consequent  escape  of  its  naked  body  into  the  plasma, 
occurs  when  slides  containing  the  live  filariae  are  kept  for  some 
hours  in  a  cold  (not  freezing)  place.  It  commonly  happens  that 
just  before  the  death  of  the  parasite  an  occasional  erythrocyte  or 
leucocyte  becomes  tightly  adherent  to  the  sheath,  swinging  to 
and  fro  with  the  now  lazy,  torpid  movements  of  the  animal. 

Technic  of  Examination. — A  rather  large  drop  of  finger 
blood,  taken  from  the  patient  late  in  the  evening,  preferably 


954 


956 


9.58 


/OOO 


FILARIASIS. 


419 


toward  midnight,  is  placed  between  a  slightly  warmed  slide  and 
cover-glass,  the  edges  of  which  are  immediately  sealed  with 
cedar  oil  or  with  vaselin.  The  parasite  should  be  searched  for 
with  a  low-power  dry  objective,  a  §-inch  lens  being  most  useful 
for  this  purpose,  and  the  attention  of  the  examiner  directed 
especially  to  portions  of  the  field  which  may  show  any  unnatural 
agitation  of  the  blood  cells.  In  specimens  prepared  in  this  man- 
ner the  filariae  will  usually  remain  active  for  several  days,  gener- 
ally for  at  least  forty-eight  hours,  and  sometimes  for  a  longer 
period,  as  in  Henry's1  experience,  this  author  having  kept  them 
alive  for  ten  days  in  a  cold  room. 

Staining  the  Filar-ice—  Films  fixed  for  fifteen  minutes  in  equal 
parts  of  absolute  alcohol  and  ether  and  stained  with  thionin 
give  the  clearest-cut  pictures,  the  multitude  of  small  nuclei  which 
crowd  the  body  of  the  filariae  being  sharply  differentiated  by  the 
use  of  this  dye.  Fixation  by  heat  or  by  formalin  cannot  be  em- 
ployed without  risk  of  injuring  the  finer  structure  of  the  embryo. 
Fair  results  may  also  be  obtained  by  staining  with  methylene - 
blue  or  with  Jenner's  or  Wright's  stain,  but  the  definition  is  not 
nearly  so  satisfactory  with  these  solutions  as  it  is  with  thionin. 
The  technic  suggested  by  Manson2  (washing  out  the  hemoglobin  of 
the  erythrocytes  with  water,  drying,  fixing  in  alcohol,  and  staining 
with  methylene-blue  or  with  hematoxylin)  has  proved  unreliable 
in  the  writer's  hands.  The  same  comment  may  be  made  re- 
garding attempts  to  demonstrate  the  structure  of  the  worm  by 
staining  wTith  fuchsin,  as  has  also  been  recommended. 

The  presence  in  the  circulation  of  the  Filaria 
Hemoglobin  nocturna  does  not  appear  of  itself  to  be  a  factor 
and         of  any  conspicuous  changes  in  the  erythrocytes 
Erythrocytes,  and   their   hemoglobin   content.     The  high- 
grade  anemia  sometimes  associated  with  filariasis, 
mentioned  by  the  Bancrofts3  and  by  Ehrlich  and  Lazarus,4  is  due, 
no  doubt,  to  such  complications  as  hematuria,  severe  chyluria,  and 
chronic  diarrhea.    In  two  cases  the  writer  found  hemoglobin 
percentages  of  85  and  88,  and  erythrocyte  counts  of  4,200,000 
and  4,876,000  per  c.mm.,  respectively.    These  figures  may  be 
taken  as  representative  for  the  average  case,  judging  from  the 
limited  data  available. 

Neither  structural  changes,  nor  irregular  staining  affinities  of 
the  cells  and  the  occurrence  of  nucleated  erythrocytes  have  been 
reported  in  connection  with  the  disease. 


1  Loc.  cit. 

3  Australasian  Med.  Gaz.,  1894,  vol.  xiii,  p.  6. 


2  Loc. 
4  Loc. 


cit. 

cit. 


420 


GENERAL  HEMATOLOGY. 


In  the  early  stages  of  filariasis  a  distinct 
Leucocytes,  leucocytosis  is  generally  found,  but  as  the  disease 
progresses  the  number  of  leucocytes  gradually 
diminishes,  and  in  cases  of  long  standing  the  count  does  not  exceed 
the  physiological .  limits  of  health,  except  as  the  result  of  some 
complication.  Thus,  in  the  first  case  quoted  above  the  leucocyte 
count  was  found  to  be  41,000  per  c.mm.,  but  this  increase  was  re- 
garded purely  as  a  post-operative  rise,  the  patient  having  been 
operated  upon  for  a  supposed  varicocele  less  than  twenty-four 
hours  before  the  blood  examination  was  made.  The  count  in  the 
second  case,  one  of  several  years'  duration,  was  8000. 

The  relative  percentage  of  mononuclear  non-granular  leuco- 
cytes is  somewhat  higher  than  normal,  with  a  consequent  decrease 
in  the  proportion  of  polynuclear  neutrophiles.  The  eosinophiles 
either  remain  at  a  maximum  normal  percentage  or  may  be  dis- 
tinctly in  excess  of  this  figure.  This  statement,  made  by  the  writer 
in  1 901,  has  since  been  verified  by  several  observers,  notably  by 
Calvert,1  Gulland,2  Coles,3  Vaquez,4  Sicard,5  and  Clerc.6  Calvert 
has  shown  that  the  eosinophilia,  like  the  leucocytosis,  diminishes 
as  the  infection  becomes  chronic,  and  that  its  development  is 
cyclical,  in  that  it  follows  by  a  few  hours  the  periodicity  of  the 
embryo  worms  in  the  peripheral  blood.  In  the  author's  two  cases 
the  percentage  of  eosinophiles  ranged  from  3.4  to  9.5 ;  in  Gulland's 
case,  from  3.0  to  12.0;  in  Calvert's  three  cases,  from  6.0  to  22.0; 
and  in  Coles'  two  cases,  from  15.0  to  17.0.  The  three  French 
authors  mentioned  above  report  eosinophilia  varying  from  7.5  to 
12  per  cent.  It  may  be  noted  here  that  the  Filaria  loa,  found  in 
the  subconjunctival  tissues,  may  also  excite  eosinophilia — 53  per 
cent,  in  a  case  reported  by  Wuntz  and  Clerc7;  and  that  in  patients 
harboring  the  guinea-worm  a  similar  eosinophile  increase  de- 
velops—as high  as  36.6  per  cent,  in  cases  studied  by  Balfour.8 
In  six  cases  of  guinea-Avorm  infection  Powell9  found  eosinophile 
percentages  of  4.7,  5.5,  7.5,  7.5,  8,  and  12.2,  respectively.  The 
lymphocytes  frequently  appear  as  cells  having  a  deeply  stained 
eccentric  nucleus  surrounded  by  an  abnormally  large  area  of 
protoplasm,  the  general  appearance  of  these  cells  being  similar 
to  those  in  the  illustration  shown  on  page  320,  Fig.  55.  Typical 
coarsely  granular  mast  cells  may  be  found  in  small  numbers 
or  they  may  be  entirely  absent,  as  may  also  be  the  finely  gran- 

1  Johns  Hopkins  Hosp.  Bull.,  1902,  vol.  xiii,  pp.  23  and  133;  also  Jour.  Amer. 
Med.  Assoc.,  1902,  vol.  xxxix,  p.  1523. 

2  Brit.  Med.  Jour.,  1902,  vol.  i,  p.  831.  3  Ibid.,  1902,  vol.  i,  p.  1137. 
4  Sera,  med.,  1902,  vol.  xxii,  p.  418.  5  hoc.  eit. 

6  Loc.  cit.  7  Sem.  med.,  1903,  vol.  xxiii,  p.  420. 

8  Lancet,  1903,  vol.  ii,  p.  1649.  9  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  73. 


GASTRITIS. 


421 


uiar  forms  of  basophilcs.  The  presence  of  myelocytes  has  not 
been  noted. 

The  detection  of  the  Filaria  noctuma  in  the 
Diagnosis,  blood  serves  at  once  to  differentiate  idiopathic 
from  parasitic  chyluria,  hydrocele  from  lymph 
scrotum,  hernia  and  other  tumors  0}  the  groin  from  parasitic 
inguinal  varicosities  (Bancroft's  "  helminthoma  elastica"),  and 
filarial  orchitis  from  other  inflammatory  conditions  of  the  testes. 
Non-parasitic  lymphedema,  affecting,  for  example,  the  legs,  can 
but  rarely  be  distinguished  by  the  blood  findings  from  true  elephan- 
tiasis Arabum,  since  in  the  latter  disease  it  is  exceptional  to  find 
filariae  in  the  general  circulation. 


XXVI.  FRACTURES. 

Blake,  Hubbard,  and  Cabot1  conclude,  from  a  study  of  38 
cases,  that  in  simple  uncomplicated  fractures  the  number  of  leu- 
cocytes is  seldom  increased  to  any  extent,  a  statement  which  applies 
also  to  complicated  fractures  in  the  great  majority  of  instances. 
Of  23  simple  fractures  examined  by  these  authors,  in  but  10  was 
the  count  higher  than  10,500  per  c.mm.,  and  of  these,  only  6 
exceeded  12,000.  The  highest  estimate  was  15,400,  in  a  fracture 
of  the  pelvis,  and  the  next  highest,  14,800,  in  a  broken  leg.  Of 
15  complicated  fractures,  but  2  showed  any  decided  increase 
in  the  number  of  leucocytes,  namely,  a  fracture  of  the  tibia  and 
fibula,  with  symptoms  suggestive  of  fat  embolism,  in  which  the 
count  was  15,600;  and  a  case  of  fractured  ribs  with  injury  of  the 
lung,  in  which  the  leucocytes  numbered  14,900  two  days  after 
the  accident.  An  estimate  of  5400  cells  was  made  in  a  compound 
fracture  of  the  leg  two  hours  after  the  accident. 

Lipemia  is  occasionally  met  with  in  fractures  of  the  long  bones 
involving  injury  of  the  fatty  marrow. 


XXVII.  GASTRITIS. 

In  the  acute  form  there  is  no  deviation  from 
Hemoglobin  normal  in  the  number  and  hemoglobin  value  of 
and         the  erythrocytes,  except  in  the  event  of  hyper- 
Erythrocytes.  emesis,  which,  through  concentration  of  the  blood, 
may  cause  a  transient  polycythemia.    In  the 
chronic  form  secondary  anemia  frequently  develops,  and  occasion- 
ally reaches  an  extreme  grade,  should  the  gastric  lesion  be  suffi- 

1  Annals  of  Surg.,  1901,  vol.  xxxiv,  p.  361. 


422 


( i K NKRAL  H E M ATO LOGY . 


cient  to  interfere  radically  with  the  digestion  and  absorption  of 
food.  In  instances  of  this  sort  the  quantitative  changes  may 
simulate  those  of  true  pernicious  anemia,  but  the  qualitative 
changes  typical  of  this  disease  are  invariably  wanting.  In  pass- 
ing, it  seems  pertinent  to  recall  the  reputed  etiological  relationship, 
distinguished  by  some  authorities,  between  gastric  tubule  atrophy 
and  pernicious  anemia.  Well-defined  secondary  anemia  (without 
erythroblasts)  was  found  by  Einhorn1  in  but  4  of.  15  cases  of  gastric 
achylia,  but  in  none  were  the  qualitative  blood  changes  of  perni- 
cious anemia  detected.  In  cases  associated  with  gastrectasis 
and  hyperacidity,  blood  inspissation  from  emesis  is  a  common 
change. 

A  synopsis  of  J.  A.  Lichty's  studies2  of  the  hemoglobin  and 
erythrocytes  in  98  cases  of  various  gastric  disorders  shows  the 
following  average;  values : 


Condition. 

Number  of 

Hemoglobin 

Erythrocytes 

Cases. 

Percentage. 

PER  C.MM. 

Hyperchlorhydria  .  . 

39 

90.9 

5,556,000 

Hypochlorhydria  . . . 

13 

83-5 

5,431,000 

Gastric  achylia   

6 

92.1 

5,680,000 

Gastric  dilatation  . . 

11 

85.6 

5,623,000 

Gastric  neurasthenia 

13 

87.2 

5,274,000 

Chronic  gastritis .... 

14 

91.0 

5,498,000 

From  other  investigations,  Lichty  also  determined  that  in  the 
above-named  diseases  there  is  no  definite  relationship  between 
the  condition  of  the  blood,  the  urine,  and  the  gastric  contents. 

In  gastroptosis  the  blood  remains  normal  in  the  great  majority 
of  patients;  in  small  proportion  either  a  mild  secondary  anemia 
or  a  chlorotic  blood  picture  develops.  Francine3  found  the  latter 
change  in  3  of  100  cases.  Of  55  patients  studied  by  Steele 
and  Francine,4  the  color  index  averaged  0.95  in  24,  0.9  in  20,  and 
fell  as  low  as  0.50  in  but  a  single  instance.  The  theory  of  Meinert,5 
that  chlorosis  is  a  factor  of  gastroptosis,  has  no  foundation  in  fact. 

In  acute  gastritis  leucocytosis  of  the  poly- 
Leucocytes.  nuclear  neutrophile  type  is  common,  although 
not  constant;  the  increase  is  most  notable  in  the 
severest  cases,  but  even  in  these  the  count  seldom  exceeds  15,000 
or  20,000.    Hyperinosis  also  usually  exists.    In  chronic  cases 

1  Med.  Rec,  1903,  vol.  lxiii,  p.  321.       2  Phila.  Med.  Jour.,  1899,  vol.  hi,  p.  326. 

3  Proc.  Phila.  Co.  Med.  Soc,  1902,  vol.  xxiii,  p.  447. 

4  Jour.  Amer.  Med.  Assoc.,  1902,  vol.  xxxix,  p.  11 73. 

5  "Zur  Aetiologie  der  Chlorose,"  Wiesbaden,  1894. 


GASTRIC  ULCER. 


423 


an  absence  of  leukocytosis  is  the  rule,  while  leucopenia,  resulting 
from  defective  absorption,  is  an  occasional  finding.  Relative 
lymphocytosis  is  commonly  associated  with  leucopenia  and 
sometimes  with  normal  leucocyte  counts.  In  a  small  proportion 
of  cases  digestion  leucocytosis  is  either  delayed  or  absent. 

The  presence  of  a  leucocytosis  is  a  valuable 
Diagnosis,    sign  in  ruling  out  enteric  fever,  should  the  diag- 
nosis lie  between  this  disease  and  acute  febrile 
gastritis.    This  sign,  however,  cannot  be  employed  to  differentiate 
other  acute  infections,  such,  for  instance,  as  appendicitis. 

The  blood  furnishes  no  sure  means  of  differentiating  chrome 
gastritis  from  gastric  cancer,  although  a  persistent  leucocytosis  is 
very  suggestive  of  the  latter;  unfortunately,  digestion  leucocytosis 
is  neither  constantly  absent  in  cancer  nor  invariably  present  in  gas- 
tritis. 

Certain  cases  of  chronic  gastric  catarrh,  with  atrophy  of  the 
stomach  tubules,  in  course  of  time  develop  a  clinical  picture  very 
like  that  of  true  pernicious  anemia,  since  they  present  not  only  a 
similar  cachexia,  but  also  a  very  striking  diminution  in  hemo- 
globin and  erythrocytes.  But  pernicious  anemia  is  characterized 
by  the  presence  of  nucleated  erythrocytes  the  majority  of  which 
are  megaloblasts,  while  in  the  secondary  anemia  of  gastric  catarrh 
erythroblasts  are  uncommon,  and  if  present,  show  a  predominance 
of  cells  of  the  normoblastic  type. 


XXVIII.  GASTRIC  ULCER. 

The  average  case  shows  a  loss  of  approxi- 
Hemoglobin  mately  40  per   cent,  of   hemoglobin  and  of 
and         1,250,000  erythrocytes  to  the  c.mm.,  and,  owing 
Erythrocytes,  to  this  prevalence  of  a  disproportionately  large 
oligochromemia,  low  color  indices  are  the  rule. 
The  individual  case  may  show  a  much  greater  degree  of  anemia, 
but  no  matter  how  marked  the  cellular  decrease,  it  is  always  far 
outstripped  by  the  diminution  in  the  percentage  of  hemoglobin. 
In  fact,  in  some  instances  the  latter  alone  is  subnormal,  the  blood 
condition  of  chlorosis  being  thus  faithfully  counterfeited.  The 
average  index  for  the  cases  tabulated  below  was  0.75. 

Profuse  hemorrhage  may  provoke  a  very  marked  anemia,  while 
protracted  emesis  tends  to  concentrate  the  blood,  thus  masking 
its  real  condition. 

The  several  degenerative  changes  affecting  the  erythrocytes 
common  to  any  severe  anemia  may  be  present  if  the  blood  de- 


424 


GENERAL  HEMATOLOGY. 


teri oration  is  sufficiently  profound.  After  a  severe  hemorrhage 
a  few  normoblasts  not  infrequently  appear  in  the  blood  tempo- 
rarily, and  an  occasional  cell  of  this  type  may  be  found  at  other 
times  in  cases  with  marked  cachexia. 

The  following  summary  illustrates  the  hemoglobin  and  eryth- 
rocyte ranges  in  33  cases: 


Hemoglobin       Number  of  Erythrocytes  Number  of 

Percentage.  Cases.  per  c.mm.  Cases. 

From  80-90  5  Above  5,000,0000  . . .    2 

"     70-80  5  From  4,000,000-5,000,000. .  .16 

"     60-70  7  "     3,000,000-4,000,000...  7 

"     50-60  1  "     2,000,000-3,000,000...  7 

"     4°-5°  6  "     1, 000,000-2, 000,00c. . .  1 

"     30-40  ;-..5 

"     20-30  4 

Average,     57  per  cent.  Average,     3,798,000  per  c.mm. 

Maximum,  89   "    "  Maximum,  5,200,000    "  " 

Minimum,  20   "    "  Minimum,  1,090,000   "  " 


Futcher 1  gives  the  following  data  of  82  cases :  the  hemoglobin 
percentage  in  42  cases  averaged  58,  ranging  from  12  to  105; 
the  erythrocyte  count  in  44  cases  averaged  4,071,000,  or  from 
1,012,000  to  4,071,000;  and  the  leucocyte  count  in  45  cases 
averaged  7500,  varying  from  1100  to  40,000. 

Greenough  and  Joslin2  report  hemoglobin  estimates  in  73  cases, 
of  which  34  were  below  50  per  cent,  and  64  below  80  per  cent. 
Of  their  43  erythrocyte  counts,  24  were  below  4,000,000  per 
c.mm.,  the  color  index  for  this  series  averaging  0.67,  and  ranging 
from  0.35  to  1. 41. 

Absence  of  leucocytosis  is  the  rule,  for  an 
Leucocytes,  increase  occurs  only  after  taking  food  or  in  the 
event  of  some  complication,  such  as  hemor- 
rhage or  perforation.  But  the  fact  must  be  recalled  that  hemor- 
rhage by  no  means  invariably  raises  the  count;  for  example,  hem- 
atemesis  is  a  symptom  in  fully  50  per  cent,  of  patients  suffering 
from  ulcer  of  the  stomach,  yet  in  not  more  than  30  per  cent,  of 
all  cases,  both  those  with  and  those  without  this  symptom,  does 
the  number  of  leucocytes  exceed  10,000  to  the  c.mm.  Perforation 
always  excites  leucocytosis,  except  when  the  patient  is  over- 
whelmingly toxic. 

1  Amer.  Med.,  1904,  vol.  viii,  p.  53. 

2  Amer.  Jour.  Med.  Sci.,  1899,  vol.  cxviii,  p.  167. 


GLANDERS. 


425 


The  behavior  of  the  leucocytes  in  the  above-mentioned  series 
of  cases  may  be  expressed  thus: 

Leucocytes  per  c.mm.  Number  of  Cases. 

Above  20,000    2 

From  15,000-20,000    2 

"    10,000-15,000    6 

"      5,000-10,000   18 

Below  5,000   5 

Average,      8,778  per  c.mm. 

Maximum,  29,400  " 

Minimum,    2,400  " 

In  cases  with  leucocytosis  the  increase  affects  chiefly  the  poly- 
nuclear  neutrophiles ;  in  those  without  leucocytosis  minimum  nor- 
mal or  distinctly  subnormal  percentages  of  these  cells  are  not 
uncommon,  and  a  total  absence  of  eosinophiles  is  the  general  rule, 
these  changes  being  counterbalanced  by  a  proportionate  increase 
in  the  small  lymphocytes. 

Hematology  gives  no  aid  in  distinguishing  gas- 

Diagnosis.  trie  ulcer  from  gastralgia,  duodenal  ulcer,  and 
simple  gall-stone  colic,  in  all  of  which  leucocytosis 
is  absent.  A  well-defined  leucocytosis  points  to  acute  gastritis 
rather  than  to  ulcer.  The  differences  in  the  blood  pictures  of 
gastric  ulcer  and  cancer  are  referred  to  under  the  latter  disease. 
(See  "Malignant  Disease.") 


XXIX.  GLANDERS. 

Data  are  wanting  regarding  the  condition  of  the  hemoglobin  and 
erythrocytes  in  human  glanders,  but  it  is  known  that  leucocytosis  is 
the  rule.  The  Bacillus  mallei  has  been  obtained  by  antemortem 
blood  culturing  and  by  Duval1  and  by  von  Jaksch.2  Heanley3 
claims  that,  with  a  dilution  of  1  12500  and  a  time  limit  of  twelve 
hours,  a  specific  serum  reaction  occurs  with  the  bacillus  of  glan- 
ders and  glanders  blood  serum.  In  lower  dilutions  similar  results 
may  be  obtained  with  the  serum  of  patients  suffering  from  variola 
and  scarlatina. 

1  Arch,  de  med.  exper.,  1896,  vol.  viii,  p.  361. 

2  "Clinical  Diagnosis,"  4th  ed.,  London,  1899. 

3  Lancet,  1904,  vol.  i,  p.  364. 


426 


GENERAL  H EM ATOLOGY. 


XXX.  GONORRHEA. 

The  hemoglobin  and  erythrocytes  are  unaltered,  but  the  acute 
febrile  stage  of  specific  urethritis  is  usually  accompanied  by  a 
moderate  poly  nuclear  leucocytosis,  which,  in  the  event  of  any  of 
the  inflammatory  complications  of  clap,  may  be  much  aggravated. 
Sabraz^s 1  found  that  the  increase  usually  does  not  exceed  double 
the  mean  average  normal  count.  Giorgi,2  contrary  to  general 
opinion,  found  an  absence  of  leucocytosis,  sometimes  leucopenia, 
the  rule,  together  with  a  relative  mononucleosis,  at  the  expense 
of  the  polynuclear  neutrophiles.  Some  authors  formerly  claimed 
that  circulatory  eosinophilia  was  a  feature  of  this  disease,  but  the 
investigations  of  Vorbach3  have  shown  that  such  a  change,  while 
occurring  sometimes,  is  by  no  means  constant;  he  found  in  20 
cases  that  the  percentage  of  eosinophiles  ranged  from  as  low  as 
0.05  to  as  high  as  11. 5.  Bettmann4  believes  that  eosinophilia  is 
especially  frequent  in  posterior  urethritis,  an  observation  which 
thus  far  is  unique. 

In  gonorrheal  endocarditis  and  in  gonorrheal  arthritis  the 
gonococcus  has  been  repeatedly  cultured  from  the  blood  during 
life.  In  distinguishing  gonorrheal  arthritis  from  rheumatic  fever  a 
positive  iodin  reaction  is  suggestive  of  the  former. 


XXXI.  GOUT. 

Garrod's 5  earlier  teachings  regarding  the  lowered  alkalinity  of 
the  blood  in  acute  gout  have  been  contradicted,  apparently  with 
ample  proof,  by  the  later  researches  of  Levy,6  who  failed  to  find 
a  diminution  in  any  of  the  17  cases  which  he  investigated  by  the 
most  approved  methods.  Still  more  recently  Levy's  conclusions 
have  been  corroborated  by  Watson.7  During  an  acute  gouty 
seizure  hyperinosis  is  an  almost  invariable  finding. 

It  is  questionable  whether  or  not  the  amount  of  uric  acid  in  the 
blood  is  greater  during  the  acute  stages  than  in  the  interval  be- 
tween them,  but  it  is  nevertheless  a  fact  that  in  many  gouty  persons 
uric  acid  crystals  can  be  demonstrated  in  the  blood  by  the  "  thread- 
test" — a  reaction  by  no  means  peculiar  to  this  disease,  as  already 
pointed  out.    (See  p.  144.) 

1  Sem.  med.,  1902,  vol.  xxii,  p.  435. 

2  Ibid.,  1904,  vol.  xxiv,  p.  39.  3  Inaug.  Dissert.,  Wurzburg,  1895. 
*  Arch.  f.  Dermat.  u.  Syph.,  1899,  vol.  xxxix,  p.  227. 

5  "Gout  and  Rheumatic  Gout,"  London,  1876,  p.  80. 

6  Zeitschr.  f.  klin.  Med.,  1898,  vol.  xxxvi,  p.  336. 

7  Brit.  Med.  Jour.,  1900,  vol.  i,  p.  10. 


[  \  l'.MOR  RH  AC.LC  DISKASES. 


The  cellular  elements  show  no  characlcrislic  alterations^  and 
are  normal,  except  in  long-standing  cases,  in  which  an  ordinary 
secondary  anemia  may  develop  in  the  course  of  time.  During 
the  acute  attack  a  moderate  increase  in  the  number  of  leucocytes, 
affecting  chiefly  the  polynuclear  neutrophiles,  may  or  may  not  be 
found.  A  relative  increase  in  the  eosinophiles  is  also  sometimes 
encountered,  in  cases  both  with  and  without  an  increase  in  the 
leucocyte  count.  In  one  case  of  the  writer's  the  blood  examined 
during  the  height  of  a  severe  paroxysm  showed  100  per  cent,  of 
hemoglobin,  7,125,000  erythrocytes,  and  14,000  leucocytes  per 
c.mm.,  the  only  peculiar  differential  change  being  the  presence  of 
myelocytes  in  the  proportion  of  0.4  per  cent.  The  occurrence  of 
these  cells  in  gout  has  also  been  mentioned  by  Watson,1  who 
found  them  in  small  numbers  both  during  and  between  the  acute 
seizures. 

The  same  observer  also  states  that  he  found  (apparently  in 
increased  numbers)  cells  resembling  blood  plaques  as  large  as  4  ^ 
in  diameter,  often  forming  "very  irregular,  torn-looking  masses." 

•The  worthlessness  of  Neusser's  so-called  perinuclear  basophilic 
granules  as  a  diagnostic  sign  of  gout  has  been  alluded  to  in  a 
previous  section  (p.  228). 

XXXII.  HEMORRHAGIC  DISEASES. 

From  a  hematological  standpoint  scurvy,  hem- 

General     ophilia,  and  the  various  forms  of  purpura  may 
Features,     conveniently  be  considered  together,  since  the 
blood  changes  in  all  of  these  conditions  are  simi- 
lar, and  in  none  are  characteristic. 

The  specific  gravity  of  the  blood  varies  with  the  degree  of 
anemia  present,  but  only  in  exceptional  instances  does  it  fall  to  an 
excessively  low  figure.  Aiello2  estimated  it  as  low  as  1.043  in 
a  case  of  purpura  hemorrhagica  in  which  the  erythrocyte  loss 
ranged  between  50  and  60  per  cent.  The  same  investigator  also 
detected,  by  spectroscopical  examination,  methemoglobin  in  the 
blood  in  this  form  of  purpura,  which  he  attributes  directly  to  auto- 
intoxication from  the  absorption  of  the  products  of  decomposition 
occurring  within  the  intestinal  canal.  Immerman3  believed  that 
in  the  late  stages  of  hemophilia  an  increase  in  the  total  quantity 
of  the  blood,  or  a  true  plethora,  exists,  but  this  view  is  not  enter- 
tained at  the  present  time. 

Various  bacteria,  especially  streptococci,  staphylococci,  and 

1  Loc.  cit.  2  Rif-  nied.,  1894,  vol.  ii,  p.  103. 

3  Ziemssen's  Handb.  spec.  Pathol,  u.  Ther.,  1879,  vol.  xiii,  p.  2. 


428 


GENERAL  HEMATOLOGY. 


bacilli,  have  been  found  in  the  circulating  blood  by  a  number  of 
observers,  both  in  scurvy  and  in  those  forms  of  purpura  due  to 
infectious  diseases.  No  special  clinical  significance,  however,  can 
be  attached  to  these  findings.  The  specific  properties  claimed  by 
Letzerich  1  for  his  Bacillus  pur  puree  are  not  generally  credited. 

The  alkalinity  of  the  blood,  according  to  the  studies  of  Cantani 2 
and  others,  is  generally  decreased  in  the  hemorrhagic  diatheses, 
although  more  recent  investigators  have  disputed  this  fact,  having 
found  it  higher  than  normal.  Wright,3  judging  from  his  studies 
of  the  blood  alkalinity  in  7  cases  of  scurvy,  believes  the  disease 
to  be  a  condition  of  acid  intoxication.  He  found  in  3  of  these  cases 
that  the  alkalinity  corresponded  to  the  figure  N.  100,  and  to  N.  200, 
N.  150,  N.  no,  and  N.  80,  respectively,  in  the  remaining  4.  As 
determined  by  this  author's  method,  the  alkalinity  of  normal  blood 
is  expressed  by  the,  formula  N.  35,  which  means,  in  other  words, 
that  the  degree  of  alkalinity  is  such  that  a  mixture  of  one  volume 
of  a  thirty- five-fold  diluted  normal  acid  with  an  equal  volume 
of  blood  serum  is  just  sufficient  to  prevent  the  latter  from 
reacting  with  sensitive  blue  litmus-paper.  Opposed  to  Wright's 
views  are  the  results  obtained  by  Lamb,4  who,  in  a  study  of  n 
cases  of  scurvy,  found  no  diminution  in  the  alkalinity  of  the 
blood.  His  cases  were  investigated  by  Wright's  method,  and 
showed  alkalinity  values  ranging  between  N.  30  and  N.  35. 

The  coagulation  of  the  fresh  blood  drop  is,  as  a  rule,  slow,  and 
sometimes  incomplete,  these  characteristics  being  observed  with 
especial  frequency  in  hemophilics.  In  such  subjects  Wright5 
determined  that  clotting  may  fail  to  occur  until  after  the  lapse  of 
over  an  hour  after  the  withdrawal  of  the  blood  from  the  vessels, 
while  in  other  instances  the  coagulation  time  ranged  from  nine 
to  fourteen  minutes.  In  8  cases  of  scurvy  Lamb6  found  that 
the  coagulation  time  ranged  from  one  and  one-quarter  to  four 
minutes,  and  averaged  about  three  and  one-half.  An  average 
clotting  time  of  four  and  one-third  minutes  was  found  by  Hutchin- 
son in  5  cases  of  infantile  scurvy.7  Of  5  cases  of  purpura 
studied  by  Sicard,8  but  one  showed  clot  retraction  with  exudation 
of  serum.  Grawitz9  has  called  attention  to  the  fact  that  in  cases 
with  long- continued  hemorrhage  the  clotting  may  be  abnormally 
rapid,  as  is  the  case  with  normal  blood  after  this  accident.  This, 
however,  must  be  an  exception  to  the  general  rule,  for,  unlike 

1  Zeitschr.  f.  klin.  Med.,  1890,  vol.  xviii,  p.  517. 

2  "Spec.  Pathol,  u.  Ther.  der  Stoffwechselkrankh.,"  Leipsic,  1884. 

3  Lancet,  1900,  vol.  ii,  p.  1556. 

4  Ibid.,  1902,  vol.  i,  p.  10.  5  Brit.  Med.  Jour.,  1893,  vol.  i,  p.  223. 
6  Loc.  cit.                                            7  Lancet,  1904,  vol.  i,  p.  1261. 

8  Amer.  Jour.  Med.  Sci.,  1899,  vol.  cxviii,  p.  466.  9  Loc.  cit. 


hemorrhagic  diseases. 


429 


normal  blood,  that  of  hemophilics  generally  clots  more  and  more 
imperfectly  as  the  amount  of  the  hemorrhage  increases.  This  is 
also  true  of  Werlhoff's  purpura,  according  to  Roncagliolo.1 

There  are  no  characteristic  changes  affecting 

Hemoglobin  the  erythrocytes  and  hemoglobin,  the  blood  pic- 
and  ture  being  that  of  secondary  anemia  of  variable 
Erythrocytes,  intensity.  In  the  majority  of  well-marked  cases 
the  erythrocytes  do  not  suffer  a  loss  of  more  than 
1,000,000  or  2,000,000  to  the  c.mm.,  but  the  hemoglobin  tends 
toward  a  proportionately  greater  decrease,  making  a  low  color 
index  the  rule.  This  is  particularly  noticeable  in  scurvy,  in  which 
condition  the  hemoglobin  loss  is  often  twice  as  great  as  that  of  the 
cells;  in  fact,  some  cases  show  simply  oligochromemia,  with  a 
normal  number  of  erythrocytes.  In  seven  cases  of  infantile  scurvy 
examined  by  the  writer  the  hemoglobin  percentage  ranged  between 
35  and  65,  averaging  43.8,  and  the  erythrocyte  count  between 
2,950,000  and  5,100,000  per  c.mm.,  the  average  being  3,527,071. 
In  three  of  these  cases,  with  counts  of  5,100,000,  4,900,000,  and 
4,814,000,  respectively,  the  corresponding  hemoglobin  estimates 
were  52,  50,  and  65  per  cent.  In  severe  cases,  for  example,  of 
scurvy  and  purpura  hemorrhagica  the  count  may  fall  to  less  than 
1,000,000  and  the  hemoglobin  to  20  per  cent,  or  lower,  these 
changes  being  accompanied  by  all  the  qualitative  alterations 
typical  of  a  profound  secondary  anemia  which  sooner  or  later 
may  prove  fatal.  Muir2  reports  a  case  of  purpura  in  which  the 
hemoglobin  was  only  n  per  cent.,  and  the  erythrocytes  800,000 
per  c.mm.  Still  more  remarkable  is  the  anemia  reported  by 
Talley3  in  a  case  of  scurvy — 17  per  cent,  of  hemoglobin  and 
370,000  erythrocytes  per  c.mm.  In  mild  cases  the  blood  may 
be  absolutely  normal  in  every  respect.  Regeneration  is  rapid  in 
cases  which  pursue  a  favorable  course.  It  is  well  known  that 
hemophilics  appear  to  be  less  susceptible  to  the  ill  effects  of 
hemorrhage  than  other  individuals,  and  thaf  in  this  condition 
recovery  from  blood  losses  is  usually  rapid  and  uneventful,  in 
spite  of  their  number,  extent,  and  chronicity. 

The  leucocytes  are  usually  increased  both  in 

Leucocytes,  purpura  and  in  scurvy,  but  in  hemophilia  a  de- 
cided leucopenia  may  develop  in  spite  of  the  ex- 
isting hemorrhages.    The  increase  is  typically  polynuclear  in 
most  instances,  although  a  relative  excess  of  lymphocytes  may 
occur.    Stengel4  found  this  change  most  striking  in  two  cases  of 

'Sem.  med.,  1903,  vol.  xxiii,  p.  368.        2  Brit.  Med.  Jour.,  1900,  vol.  ii,  p.  909. 

3  Jour.  Amer.  Med.  Assoc.,  1902,  vol.  xxxix,  p.  1086. 

4  "Twentieth  Century  Practice  of  Medicine,"  New  York  1896,  vol.  vii,  p.  485. 


.  43° 


GENERAL  HEMATOLOGY. 


purpura  hemorrhagica,  and  the  writer  has  noticed  an  exaggeration 
of  the  lymphocytic  tendency  of  children's  blood  in  a  number  of 
cases  of  infantile  scurvy.  In  4  of  the  7  cases  of  this  condition 
referred  to  in  the  preceding  paragraph,  the  total  percentage  of 
lymphocytes  was  between  60  and  66;  in  3  the  percentage  of 
poly  nuclear  neutrophiles  was  from  27  to  35;  the  eosinophiles  aver- 
aged a  low  normal  figure,  and  in  all  but  a  single  case  myelocytes 
were  found,  ranging  in  percentage  from  a  minimum  of  1  to  a 
maximum  of  6,  and  averaging  2.5  per  cent.  The  actual  number 
of  leucocytes  varied  between  8000  and  25,000,  and  averaged 
15,557  per  c.mm.,  all  but  a  single  case  having  a  decided  increase. 
Denys1  has  called  attention  to  the  presence  of  large  numbers  of 
leucocytes  in  the  different  stages  of  degeneration,  both  in  scurvy 
and  in  the  infectious  form  of  purpura. 

'  In  all  the  hemorrhagic  conditions  above  men- 
Blood       tioned  the  blood  plaques  are  usually  much  di- 
Plaques.     minished  in  number  and  sometimes  are  absent. 

Especially  is  this  the  case  in  grave  forms  of 
scurvy  and  of  purpura  hsemorrhagica.  Hayem2  believes  that  a 
marked  diminution  in  the  number  of  plaques  plus  a  deficiency  in 
clotting  is  a  pathognomonic  sign  of  the  latter  disease.  Lenoble3 
considers  that  in  all  cases  of  true  purpura  the  plaques  are  increased 
in  size  but  diminished  in  number,  and  that  (as  in  malarial  fever) 
they  lose  their  characteristic  viscidity  and  consequently  their  race- 
mose grouping.  These  peculiarities,  plus  the  presence  of  normo- 
blasts and  the  failure  of  the  blood  clot  to  retract,  this  author 
believes  to  be  the  specific  hematological  formula  of  this  disease, 
whatever  may  be  its  clinical  variety. 

XXXIII.    HEPATIC  CIRRHOSIS. 

In  the  early  stages  of  atrophic  cirrhosis,  so  long 
Hemoglobin  as  the  patient's  general  health  is  maintained,  the 
and         blood  remains  practically  normal,  or  shows,  per- 
Erythrocytes.  haps,  only  a  moderate  diminution  in  hemoglobin. 

But  as  the  disease  progresses  and  the  patient 
suffers  from  gastro-intestinal  catarrh,  hemorrhages,  and  circulatory 
embarrassment,  an  ordinary  secondary  anemia  sooner  or  later 
becomes  apparent,  the  intensity  of  this  change  depending  upon 
the  severity  of  the  primary  disease  and  its  associated  lesions. 
Most  advanced  cases  show  a  loss  of  from  2,000,000  to  3,000,000 

1  Centralbl.  f.  allg.  Pathol,  u.  path.  Anat.,  1893,  vol.  iv,  p.  174. 

2  Compt.  rend.  l'Acad.  sc.,  Paris,  1896,  vol.  exxiii,  p.  894. 

3  Sem.  med.,  1902,  vol.  xxii,  p.  355. 


HEPATIC  CIRRHOSIS. 


43 1 


cells  to  the  c.mm.,  and  a  few,  an  even  greater  oligocythemia. 
Hemorrhages,  either  repeated  and  small  or  single  and  profuse, 
constitute  the  factor  of  a  profound  anemia  in  many  instances. 
The  average  case  of  Laennec's  cirrhosis  loses  about  40  per  cent, 
of  hemoglobin  and  30  per  cent,  of  erythrocytes,  while  in  the 
individual  case  the  count  may  fall  to  between  1,500,000  and 
2,000,000.  The  color  index,  as  a  rule,  is  moderately  reduced;  it 
averaged  0.86  for  a  series  of  40  well-advanced  cases  examined  at 
the  German  Hospital,  a  synopsis  of  which  shows  these  hemoglobin 
and  erythrocyte  values : 


Hemoglobin  Number  of 
Percentage.  Cases. 

From  90-100  1 

"    80-90  6 

"    70-80  8 

"    60-70  5 

"    50-60  8 

40-50  7 

"    30-40  5 

Average,     60.4  per  cent, 
Maximum,  98.0  "  " 
Minimum,  30.0  "  " 


Erythrocytes 
per  C.MM. 


Number  of 
Cases. 


From  4,000,000-5,000,000. . .  10 
"  3,000,000-4,000,000  -.18 
"  2,000,000-3,000,000. ..  10 
"     1,000,000-2,000,000...  2 


Average,     3,526,825  per  c.mm. 
Maximum,  4,970,000  "  " 
Minimum,  1,800,000  "  " 


The  effects  of  ascites  upon  the  blood  are  probably  twofold  and 
diametrically  opposed.  Primarily  it  is  thought  to  cause  more  or 
less  anemia  by  reason  of  the  steady  drain  exerted  upon  the  albu- 
min of  the  blood,  but  this  deterioration  may  be  effectually 
masked  by  a  polycythemia  due  either  to  peripheral  stasis  or  to 
inspissation  of  the  blood  caused  by  the  rapid  transudation  of 
liquids  from  the  vessels.  This  last  factor  is  no  doubt  the  cause 
of  the  polycythemia  noted  by  von  Limbeck1  in  cases  after  para- 
centesis. On  the  other  hand,  Grawitz2  has  demonstrated  that  a 
decrease  in  the  hemoglobin  and  erythrocyte  values  may  follow 
this  operation,  in  cases  in  which  the  presence  of  a  large  ascitic 
exudate  interferes  with  the  circulation  sufficiently  to  produce 
capillary  stagnation  and  a  consequent  polycythemia,  which  the 
tapping  dispels. 

Anemia  is  apparently  more  striking  and  more  common  in 
hypertrophic  cirrhosis  than  in  ordinary  gin-liver.  Judging  from 
a  rather  limited  experience  in  16  cases,  the  writer  finds  a 
greater  tendency  toward  corpuscular  than  toward  hemoglobin  loss, 
and  consequently  toward  higher  color  indices.    The  index  for 

1  Loc.  cit.  2  Loc.  cit- 


432 


GENERAL  HEMATOLOGY. 


these  cases  averaged  0.91,  and  in  two  it  reached  the  figures  1.02 
and  Loo,  respectively.  For  the  series  the  hemoglobin  averaged 
52.9  per  cent.,  the  minimum  being  20  and  the  maximum  85  per 
cent.  The  average  erythrocyte  count  was  2,895,324,  and  ranged 
from  as  low  as  1,100,000  to  as  high  as  4,290,000  per  c.mm. 

The  usual  degenerative  and  other  qualitative  changes  accom- 
panying any  severe  secondary  anemia  may  be  found  in  the  anemias 
of  liver  cirrhoses;  and,  in  addition,  Hayem1  has  observed  that  in 
the  hypertrophic  variety  there  seems  to  be  a  marked  tendency 
toward  megalocytosis.  It  may  here  be  noted  that  in  Hanot's 
disease  Netter2  has  detected  staphylococci  and  Kirikow3  diplo- 
cocci  in  the  peripheral  blood  during  life.  The  effect  of  bile  upon 
the  blood  is  also  apparent  in  many  cases  of  Hanot's  cirrhosis. 
(See  "  Icterus,"  p.  434.) 

;  In  the  great  majority  of  atrophic  cirrhoses  the 
Leucocytes,  number  of  leucocytes  either  remains  normal  or  is 
distinctly  decreased,  while  a  few  show  a  moderate 
degree  of  intermittent  leucocytosis,  to  be  regarded  in  all  proba- 
bility as  a  post-hemorrhagic  change.  It  is  questionable  whether 
or  not  the  jaundice  present  in  some  cases  accounts  for  a  leucocyte 
increase,  although  some  authorities  profess  this  belief.  The  leu- 
cocytes in  the  40  cases  tabulated  above  ranged  thus : 

Leucocytes  per  c.mm.  Number  or  Cases. 

From  10,000-15,000  in   4 

5,000-10,000  "  26 

Below  5,000  "  10 

Average,      6,921  per  c.mm. 
Maximum,  12,000  "  " 
Minimum,    3,000  "  " 

In  the  16  cases  of  hypertrophic  cirrhosis  the  leucocytes 
averaged  9385  per  c.mm.,  the  lowest  count  being  4100,  and  the 
highest  21,600.  Seven  of  the  estimates  were  above,  and  nine 
below,  10,000  cells  to  the  c.mm.  Much  higher  counts  than  these, 
however,  have  been  reported  by  others.  While  it  must  be  ad- 
mitted that  leucocytosis  is  more  frequent  in  this  than  in  the 
atrophic  variety,  Hanot  and  Meunier's4  claim  that  it  is  a  constant 
symptom  of  hypertrophic  cirrhosis  is  by  no  means  justified. 

The  leucocytoses  of  both  these  forms  of  the  disease  depend  • 

1  "  Du  Sang,"  Paris,  1889.  2  Progres  med.,  1886  vol.  xiv,  p.  992. 

3  St.  Petersburg  med.  Wochenschr.,  1900,  vol.  xvii,  p.  353. 

4  Compt.  rend.  Soc.  biol.,  Paris,  1895,  vol.  ii,  p.  49. 


HYDATID  DISEASE. 


433 


upon  an  absolute  and  relative  increase  in  the  polynuclear  neutro- 
phils, at  the  expense  of  the  other  forms  of  cells. 

The  blood  examination  fails  to  provide  any 
Diagnosis,    dependable  signs  by  which  cirrhosis  is  distin- 
guishable from  other  lesions  of  the  liver,  but  a 
good  idea  of  the  inroads  made  by  the  disease  upon  the  patient's 
health  may  be  gained  by  determining  from  time  to  time  the  grade 
of  the  anemia  present. 

XXXIV.    HYDATID  DISEASE. 

In  the  reported  blood  studies  of  this  condition 
Hemoglobin  the  hemoglobin  and  erythrocytes  have  varied  so 
and         greatly  that  it  seems  fair  to  regard  the  presence 
Erythrocytes,  of  an  anemia  as  due  to  factors  other  than  the 
echinococcus  infection.    Some  cases  show  per- 
fectly normal  values,  or,  at  the  most,  trifling  hemoglobin  losses, 
while  in  others  a  rather  severe  type  of  secondary  anemia  develops. 
Low  color  indices  rule. 

Leucocytosis  with  eosinophilia  is  the  impor- 
Leucocytes.  tant  feature  of  the  blood  picture.  In  Seligmann 
and  Dudgeon's  case,1  the  first  to  be  reported,  the 
leucocytes  numbered  as  high  as  17,000  per  c.mm.,  and  the  eosino- 
philes  reached  57  per  cent.,  the  actual  count  of  these  cells  being, 
therefore,  9690  to  the  c.mm.,  or  nearly  twenty  times  the  maximum 
normal  number.  Longridge's  case2  had  9  per  cent,  of  eosino- 
philes  in  a  leucocyte  count  of  18,400,  and  the  reports  of  others, 
notably  Launois  and  Weil,3  Turner  and  Milian,4  Archard  and 
Clerc,5  Darguin  and  Tribondeau,6  attest  that  this  form  of  leuco- 
cyte increase  is  constant  in  hydatid  disease,  no  matter  in  what 
region  of  the  body  the  cysts  are  situated.  As  in  other  forms  of 
helminthiasis,  the  eosinophilia  of  hydatid  disease  may  disappear 
in  cases  of  great  chronicity.  The  polynuclear  neutrophils  are 
greatly  diminished,  the  lymphocytes  remain  about  normal,  and 
the  basophiles  are  distinctly  increased.  After  evacuation  of  the 
cysts  the  leucocytosis  and  eosinophilia  promptly  disappear,  and  the 
other  forms  of  cells  again  attain  their  normal  proportions.  Memmi 7 
has  produced  eosinophilia  experimentally  by  the  injection  of 
hydatid  fluid. 

1  Lancet,  1902,  vol.  i,  p.  1764.  2  Ibid.,  1902,  vol.  ii,  p.  44. 

3  Sem.  med.,  1902,  vol.  xxii,  p.  378.  4  Ibid.,  1902,  vol.  xxii,  p.  7.5.  1 

5  Arch.  gen.  de  med.,  1902,  vol.  clxxxix,  p.  743. 

6  Presse  med.,  1902,  vol.  viii,  p.  142. 

7  Riv.  crit.  di  clin.  med.,  1901,  vol.  ii,  p.  233 

28 


434 


GENERAL  HEMATOLOGY. 


In  hydatids  versus  abscess  or  solid  tumor  the 
Diagnosis,    presence  of  eosinophilia  is  strongly  in  favor  of 
the  former,  other  eosinophile-increasing  causes 
being,  of  course,  eliminated. 


XXXV.  HERPES  ZOSTER. 

The  blood  changes  in  shingles  have  been  studied  by  Sabrazes 
and  Mathias,1  who  found  no  appreciable  diminution  in  the 
hemoglobin  and  erythrocytes  and  no  structural  changes  affecting 
the  latter.  Leucocytosis  develops  as  early  as  the  first  day  of  the 
eruption,  and  progressively  increases  until  about  the  third  day, 
after  which  it  gradually  diminishes  until,  by  the  fifth  day,  the 
count  again  reaches  the  normal  figure.  A  secondary  leucocytosis 
accompanies  the  period  of  desiccation  and  desquamation.  A  gain 
in  the  polynuclear  neutrophils  and  eosinophiles  is  accountable 
for  the  leucocytosis,  which  in  some  instances  is  associated  with  a 
few  myelocytes. 

XXXVI.  ICTERUS. 

Simple  catarrhal  jaundice  per  se  produces  little 
General  or  no  effect  upon  the  blood,  except  in  the  most 
Features,  pronounced  cases.  The  most  conspicuous  change 
consists  in  a  greenish-yellow  discoloration  of  the 
serum,  due  to  the  presence  of  bile.  In  patients  suffering  from 
obstructive  jaundice — due,  for  instance,  to  gall-stones — a  surgical 
operation  may  be  complicated  by  dangerous,  even  fatal,  hemor- 
rhage, owing  to  the  slow  and  imperfect  coagulation  of  the  blood. 
The  coagulation  time  of  the  blood  in  this  form  of  obstructive 
jaundice  is  referred  to  elsewhere.  (See  "  Cholelithiasis,"  p.  380.) 
In  the  Jefferson  Hospital  within  three  years  four  patients  with 
jaundice  due  to  malignant  disease  of  the  biliary  apparatus  have 
bled  to  death  after  operation.  The  quantity  of  fibrin  is  not  in- 
creased. The  specific  gravity  of  the  whole  blood  increases  in 
relation  to  the  intensity  of  the  icterus,  but  the  density  of  the  serum 
is  unaffected.  In  severe  cases  de  Rienzi2  found  that  the  alkalinity 
of  the  blood  was  decidedly  reduced.  The  blood  serum  of  patients 
affected  with  icterus,  especially  Weil's  disease,  may  exhibit  a 
moderate  agglutinative  action  upon  the  Eberth  bacillus,  the  colon 
bacillus,  the  cholera  spirillum,  and  other  bacteria.  Koehler3 

1  Rev.  de  sc.  med.,  1901,  vol.  xxi,  p.  251. 

2  Virchow's  Arch.,  1885,  vol.  cii,  p.  21S. 

3  Cited  by  Libman,  Med.  News,  1904,  vol.  lxxxiv,  p.  204. 


ICTERUS.  435 

attributes  this  clumping  power  to  the  taUrocholic  acid  constituent 
of  the  bile.    (See  "  Enteric  Fever,"  p.  403.) 

In  mild  cases  the  hemoglobin  and  erythrocytes 
Hemoglobin  remain  unaltered,  but  in  severe  jaundice  a  mod- 
and         erate  anemia  is  not  uncommon,  characterized  by 
Erythrocytes,  an  absence  of  rouleaux  formation  and  by  evi- 
dences of  endoglobular  degeneration  marked  out 
of  all  proportion  to  the  grade  of  the  cellular  decrease.  This 
association  of  a  moderate  oligocythemia  with  striking  degenera- 
tive changes  in  the  corpuscles  appears  to  be  peculiar  to  this  affec- 
tion.   In  cases  with  symptoms  of  cholemia  these  degenerative 
changes  are  even  more  notable,  but  here  the  hemoglobin  and 
erythrocyte  losses  also  are  more  pronounced. 

The  effects  produced  upon  the  hemoglobin  and  erythrocytes 
by  catarrhal  jaundice  are  illustrated  by  this  table  of  examinations 
in  40  cases: 


Hemoglobin         Number  of  Erythrocytes  Number  of 

Percentage.             Cases.  per  c.mm.  Cases. 

From  90-100  4  Above  5,000,000  4 

"    80-90  10  From  4,000,000-5,000,000  .-19 

"    70-80  13  "     3,000,000-4,000,000  8 

"    60-70  4  "     2,000,000-3,000,000  7 

"    50-60                2  "     1,000,000-2,000,000  2 

"    40-50   3 

"    30-40   2 

"    20-30   2 

Average,     72.0  per  cent.  Average,     3,956,000  per  c.mm. 

Maximum,  97.0     "  Maximum,  5,344,000 

Minimum,  28.0     "  Minimum,  1,500,000  " 


Von  Limbeck 1  has  observed  that  the  volume  of  the  individual 
erythrocyte  is  markedly  increased.  The  cells'  diameters,  accord- 
ing to  Vaquez,2  average  8  or  9  fx,  and  not  infrequently  are  as  large 
as  12  fi.  Originally  von  Limbeck,3  and  later  Lang4  and  Vaquez 
and  Ribierre,5  also  noted  that  in  jaundice  the  erythrocytes  are 
highly  resistant  to  the  action  of  hypotonic  sodium  chlorid  solu- 
tions and  of  distilled  water.  This  change  probably  is  preceded 
by  a  period  of  susceptibility  on  the  part  of  the  erythrocytes  to  the 
action  of  circulating  biliary  poisons,  and  its  development  suggests 
that  in  time  the  cells  acquire  a  tolerance  against  the  very  toxins 
which  primarily  acted  deleteriously  upon  them.    It  is  possible 

1  Loc.  cit.  2  Sem.  med.,  1902,  vol.  xxiii,  p.  245. 

3  Loc.  cit.  4  Zeitschr.  f.  klin.  Med.,  1902,  vol.  xlvii,  p.  153. 

5  Sem.  med.,  1902,  vol.  xxiii,  p.  246. 


436 


GENERAL  HEMATOLOGY. 


that  in  some  instances  the  anemia  is  actually  greater  than  the 
blood  count  indicates,  for  polycythemia,  according  to  Becquerel 
and  Rodier,1  may  develop  by  reason  of  inspissation  of  the  blood 
from  the  action  of  bile. 

Most  observers  report  that  no  leucocytosis 
Leucocytes,  occurs  in  simple  catarrhal  jaundice,  but  Grawitz,2 
on  the  contrary,  states  that  he  finds  a  constant 
increase  in  "uncomplicated  cases  of  icterus,"  the  count  ranging 
in  some  instances  as  high  as  from  30,000  to  40,000  to  the  c.mm. 
This  author's  report,  however,  does  not  represent  the  general 
consensus  of  opinion.  In  the  writer's  experience,  about  one-fifth 
of  all  cases  of  catarrhal  jaundice  show  a  leucocyte  count  higher 
than  10,000  to  the  c.mm.  The  following  estimates  in  40  cases 
are  the  basis  for  this  statement : 


Leucocytes  Number  of 

per  c.mm.  Cases. 

From  20,000-30,000   4 

"     15,000-20,000  o 

"     10,000-15,000   4 

"      5,000-10,000  29 

Below  5,000   3 


Average,      9>36i  per  c.mm. 
Maximum,  26,000  "  " 
Minimum,    3,600  "  " 

Severe  cases  with  cholemia  may  and  usually  do  give  rise  to  a 
well-developed  leucocytosis.  In  experimental  cholemia  in  animals, 
caused  by  the  injection  of  bile  and  of  biliary  salts  and  pigments, 
Gilbert  and  Herscher3  invariably  noted  a  decided  leucocytosis, 
the  extent  and  persistence  of  which  indexed  the  animals'  defensive 
powers  against  the  toxin. 

The  association  of  icterus  with  leucocytosis, 
Diagnosis,    except  in  obviously  cholemic  patients,  suggests 
some  purulent  lesion  or  malignant  disease  as  the 
factor  of  jaundice,  rather  than  uncomplicated  angiocholitis. 


XXXVII.  INFLUENZA. 

General  invasion  of  the  circulation  by  the  influenza  bacillus 
occurs  very  rarely,  and  the  positive  results  from  bacteriological 
examination  of  the  blood  claimed  by  Canon,4  Klein,5  and  their 

1  Arch,  de  Physiol,  norm,  et  path.,  1874,  vol.  i,  p.  509. 

2  Loc.  cit.  3  Sem.  med.,  1902,  vol.  xxii,  p.  197. 

4  Virchow's  Arch.,  1893,  vol.  exxxi,  p.  401. 

5  Baumgarten's  Jahresb.,  1893,  vol.  ix,  p.  206. 


INSOLATION. 


437 


contemporaries  must  be  regarded  as  unsubstantiated,  in  the  light  of 
the  large  number  of  negative  findings  by  Pfeiffer1  and  by  Kiihnau.2 
Slawyk3  has  recently  succeeded  in  cultivating  this  organism  from 
the  blood  of  a  patient  whose  predominant  symptoms  suggested 
epidemic  meningitis.  Castellani4  was  able  to  detect  pneumo- 
cocci,  but  not  Pfeiffer's  bacilli,  in  the  blood  of  patients  having 
influenza  complicated  by  catarrhal  and  croupous  pneumonia. 
Jehle,5  although  he  admits  the  rare  occurrence  of  the  influenza 
bacillus  in  the  blood  of  uncomplicated  influenza,  claims  to  have 
obtained  many  positive  blood  cultures  of  this  organism  in  diph- 
theria, in  pertussis,  and  in  several  of  the  exanthemata — measles, 
scarlet  fever,  and  varicella.  He  attributes  these  findings  to  the 
fact  that  these  diseases  predispose  to  a  secondary  infection,  espe- 
cially to  an  influenzal  bacteriemia. 

The  hemoglobin  and  erythrocytes  are  normal  in  the  great  ma- 
jority of  cases,  a  moderate  diminution  in  these  elements  having 
been  found  only  occasionally. 

Uncomplicated  influenza  is  one  of  the  few  examples  of  an  acute 
infection  unaccompanied  by  a  leucocytosis,  although  in  some  in- 
stances hyperinosis  may  be  observed  in  the  early  stages  of  the 
attack.  Rieder6  states  that  a  complicating  catarrhal  pneumonia 
causes  either  a  moderate  increase  in  the  number  of  leucocytes  or 
none  at  all,  but  that  in  a  post-influenzal  croupous  pneumonia  the 
leucocytosis  of  this  condition  develops  typically. 

It  is  unfortunate  that  an  absence  of  leucocytosis  is  common  to 
both  enteric  fever  and  influenza,  for  these  two  diseases  are  not  in- 
frequently confused.  The  serum  test,  however,  generally  is  con- 
clusive if  typhoid  exists,  and  blood  cultures  are  even  more  definite. 
Should  a  frank  leucocytosis  be  present,  croupous  pneumonia, 
rather  than  influenza,  is  suggested. 


XXXVIII.  INSOLATION. 

In  the  acute  stages  of  thermic  fever  the  hemoglobin  and  ery- 
throcyte values  are  unduly  high,  owing  to  the  concentration  of 
the  blood  from  the  excessive  loss  of  body  fluids  by  the  lungs  and 
the  skin.  Lambert,7  for  example,  has  observed  a  hemoglobin 
percentage  of  125  in  a  sunstroke  patient,  while  Vincent8  states 

1  Deutsch.  med.  Wochenschr.,  1893,  vol.  xix,  p.  816.  2  Loc.  cit. 

3  Zeitschr.  f.  Hyg.  u.  Infectionskr.,  1890,  vol.  xxxii,  p.  443. 

4  Fortsch.  d.  Med.,  1901,  vol.  xix,  p.  781. 

5  Zeitschr.  f.  Heilk.,  1901,  vol.  xxii,  p.  190. 

6  Munch,  med.  Wochenschr.,  1892,  vol.  xxxix,  p.  511. 

7  Loomis-Thompson,  "A  System  of  Practical  Medicine,"  New  York,  1898, 
vol.  hi,  p.  877.  s  These  d.  Bordeaux,  1887-88,  No.  8,  p.  7. 


438 


GENERAL  HEMATOLOGY. 


that  the  erythrocytes  may  number  as  high  as  300,000  per  c.mm. 
in  excess  of  the  normal  average  count.  A  more  or  less  pronounced 
destruction  of  the  erythrocytes  also  occurs  both  during  and  after 
the  acute  stages  of  insolation,  and  this  factor  is  responsible  for 
the  anemia,  sometimes  decided,  which  subsequently  develops. 
Owing  to  the  coexistence  of  these  two  conflicting  factors  the  real 
extent  of  the  hemolysis  cannot  be  determined  until  after  the 
disappearance  of  the  symptoms  leading  to  blood .  concentration. 
This  hemolysis  is  thought  to  depend  upon  the  presence  in  the 
blood  of  some  toxic  element,  since  the  hyperpyrexia  itself  is  in- 
sufficient to  cause  disorganization  of  the  cells.  Schultze  and  Ran- 
vier's 1  experiments  have  proved  that  such  changes  begin  only 
when  an  animal  is  subjected  to  a  temperature  of  from  540  to  560 
C.  (129. 20  to  132. 8°  F.).  Levene  and  Van  Gieson2  have  shown 
that  the  blood  serum  of  sunstruck  patients  is  a  highly  active  blood 
poison  to  animals  when  injected  intravenously. 

Some  investigators  have  found  an  increased  number  of  leuco- 
cytes, but  others  have  been  unable  to  detect  any  such  change,  so 
that  leucocytosis  must  be  regarded  as  an  inconstant  sign,  depend- 
ing, perhaps,  more  upon  the  degree  of  blood  condensation  than 
upon  any  specific  influence -of  the  heat-stroke.  Pigmented  leuco- 
cytes have  been  observed  in  cases  in  which  there  existed  marked 
signs  of  blood  destruction. 

Wood3  found  that  a  decreased  alkalinity  or  even  an  acidity  of 
the  blood  was  a  conspicuous  postmortem  change,  but  evidence 
is  lacking  to  show  that  the  reaction  of  the  blood  -is  altered  during 
life. 

XXXIX.  INTESTINAL  HELMINTHIASIS. 

The  presence   in    the  intestinal  canal  of 
General     certain  parasites,  notably  the  Bothriocephalus 
Features,     latus  and  the  Ankylostomum  duodenale,  is  cap- 
able of  provoking  anemia   of  marked  inten- 
sity in   the  individual  harboring   them.     The  Ascaris  lum- 
bricoides  also  may  be  held  responsible  for  anemia  in  some  in- 
stances, but  the  blood  changes  attributable  to  this  parasite  are, 
as  a  rule,  much  less  marked  than  those  commonly  met  with  in 
the  two   preceding  forms  of  helminthiasis.     Ostrovosky4  has 
called  attention  to  a  case,  unique  of  its  kind,  of  fatal  progressive 
anemia  attributable  to  the  presence  in  the  intestine  of  the  long 
threadworm,  Trichocephalus  dispar.    Severe  secondary  anemia, 

1  Cited  by  Vincent,  loc.  cit.  2  Cited  by  Lambert,  loc.  cit 

3  "Thermic  Eever  or  Sun-stroke"  (Boylston  Prize  Essay),  Philadelphia,  1872. 

4  Russkiy  Vrach  Sept.  30,  1900;  abst.,  N.  Y.  Med.  Jour.,  1900,  vol.  Ixxii,  p.  826. 


INTESTINAL  HELMINTHIASIS. 


439 


not  approaching  the  true  pernicious  type,  has  been  found  in  this 
infection  by  E.  Becker.1  The  cause  of  these  anemias  is  generally 
attributed  to  two  factors:  interference  with  absorption  of  food  from 
the  intestinal  canal  due  to  the  catarrhal  inflammation  therein 
existing,  and  the  Systemic  effects  on  the  host  of  certain  soluble 
and  absorbable  toxic  products  eliminated  by  the  parasites.  That 
such  poisons  are  produced,  and  that  they  undoubtedly  can  act  in 
this  deleterious  manner,  has  been  abundantly  proved  by  many 
different  investigators,  among  whom  Hubner,2  Reyner,3  Schau- 
mann,4  Askanazy,5  and  Lussana6  may  be  named  as  authorities 
whom  the  student  should  consult  for  more  detailed  information 
on  this  topic.  It  is  probable  that  in  ankylostomiasis  the  anemia 
is  also  kept  up  partly  by  the  constant  drain  on  the  system  caused 
by  the.  direct  abstraction  of  blood  by  the  parasite,  and  partly  by 
the  so-called  "  plasmotropic "  action  of  the  blood  derivatives  ab- 
sorbed from  the  gut.  Grawitz7  explains  this  form  of  blood  de- 
struction by  assuming  that  the  presence  of  blood  in  the  intestine 
is  attended  by  the  elaboration  of  certain  toxic  substances  which, 
when  absorbed,  influence  the  bone  marrow,  liver,  and  spleen  so 
as  to  provoke  increased  hemocytolysis.  The  details  of  this  type 
of  blood  destruction  have  been  described  by  the  writer  elsewhere.8 
The  blood  changes  due  to  Bothriocephalus 
Hemoglobin  latus  infection  are  by  far  the  most  interesting, 
and  from  the  clinician's  standpoint,  since  the  anemia 
Erythrocytes,  caused  by  this  worm  may  in  some  individuals 
exactly  simulate  primary  pernicious  anemia.  The 
blood  pictures  of  the  two  conditions  may  be  identical,  both  being 
characterized  by  marked  and  disproportionate  oligocythemia,  and 
consequently  by  a  high  color  index  and  by  the  presence  of  nucleated 
erythrocytes,  the  majority  of  which  conform  to  the  megaloblastic 
type.  Megalocytes  and  erythrocytes  stippled  with  basophilic 
areas  also  are  usually  numerous.  This  so-called  bothriocephalus 
anemia  has  been  aptly  described  by  Ehrlich9  as  "a  pernicious 
anemia,  with  a  known  and  removable  cause."  It  is  distinguishable 
from  true  pernicious  anemia  solely  by  the  fact  that  after  the  expul- 
sion of  the  worm  by  the  administration  of  appropriate  vermifuges 
the  megaloblastic  type  of  blood  and  the  anemia  rapidly  disappear, 
and  the  patient  makes  an  uneventful  recovery. 

1  Deutsch.  med.  Wochenschr.,  1002,  vol.  xxviii,  p.  468. 

2  Deutsch.  Arch.  f.  klin.  Med.,  1870,  vol.  vii,  p.  7. 

3  Ibid.,  1886,  vol.  xxxix,  p.  31.         4  "  Bothriocephalus-Anamie,"  Berlin,  1894. 

5  Zeitschr.  f.  klin.  Med.,  1893,  vol.  xxiii,  p.  80;  ibid.,  1895,  vol.  xxvii,  p.  492. 

6  Rivista  clin.,  1889,  vol.  iv,  p.  750. 

7  Deutsch.  med.  Wochenschr.,  1901,  vol.  xxvii,  p.  908. 

8  Amer.  Med.,  1902,  vol.  v,  p.  571.  9  Loc.  cit. 


1 


44© 


GKNERAL   HI';  MATOLOG  Y . 


The  anemia  of  ankylostomiasis  (uncinariasis),  while  it  may 
reach  a  very  high  grade  of  development,  still  docs  not  counterfeit 
pernicious  anemia.  Griesinger's  Egyptian  chlorosis,  the  brick- 
makers'  anemia  of  the  Germans  and  the  miners'  anemia  of  the 
Italians,  as  well  as  many  forms  of  tropical  anemia,  are  all  due 
to  the  effects  of  this  nematode.  The  hemoglobin  and  erythrocyte 
loss  may  individually  be  as  great  as  is  seen  in  Biermer's  disease, 
but  low  color  indices  rule.  The  erythrocytes  are  commonly  found 
in  a  state  of  marked  deformity,  as  to  both  shape  and  size,  poly- 
chromatophilia  may  be  noted,  and  erythroblasts  are  often  seen, 
but  never,  so  far  as  our  present  knowledge  indicates,  is  there  a 
prevalence  of  megaloblasts,  as  there  is  both  in  bothriocephalus 
and  in  pernicious  anemias. 

Save  in  ankylostomiasis,  leucocytosis  does  not 
Leucocytes,  accompany  any  of  the  above-named  forms  of 
helminthiasis,  except  as  the  effect  of  some  com- 
plication. In  ankylostomiasis  it  is  more  frequent  the  earlier  the 
stage  of  the  disease,  and  usually  disappears  by  the  time  the 
anemia  is  well  defined.  Boycott  and  Haldane's  34  cases1  ranged 
between  3800  and  56,000  per  c.mm.,  the  4  highest  (averaging 
36,250)  being  in  patients  ill  not  longer  than  six  months,  and  the 
4  lowest  (averaging  5875)  occurring  in  cases  of  from  two  to  four 
years'  standing.  Rogers2  found  an  average  count  of  5338  in  12 
cases,  and  Ashford3  an  average  of  7000  in  19  cases.  These  cases 
were  probably  of  considerable  chronicity.  Sandwith4  noted, 
contrary  to  the  general  rule,  that  the  number  of  leucocytes  in- 
creases as  the  patient  convalesces. 

As  already  pointed  out  (see  p.  256),  a  conspicuous  feature  of 
the  blood  is  the  frequent,  but  not  constant,  occurrence  of  both  a 
relative  and  an  absolute  increase  in  the  percentage  of  eosinophiles. 
This  change  is  especially  well  marked  soon  after  the  infection 
occurs,  but  may  disappear  in  time,  even  though  the  worm  is  not 
expelled — a  fact  first  proved  by  Boycott  and  Haldane,5  and  one 
to  which  may  be  attributed  the  inconstancy  of  eosinophilia  in 
helminthiasis  of  various  types.  The  individual's  age  and  resisting 
powers  are,  of  course,  contributing  factors.  The  eosinophilia  may 
be  moderate  or  it  may  be  enormous — in  one  case  of  ankylos- 
tomiasis reported  by  Ashford,6  40  per  cent.,  and  in  another, 
53.5  per  cent.;7  72  per  cent,  in  a  case  of  the  same  disease  and 
34  per  cent,  in  a  patient  harboring  the  Tcenia  mediocanellata, 

1  Jour.  Hyg.,  1903,  vol.  iii,  p.  121.  2  Brit.  Med.  Jour.,  1900,  vol.  ii,  p.  544. 

3  N.  Y.  Med.  Jour.,  1900,  vol.  lxxi,  p.  552.  4  Lancet,  1894,  vol.  i,  p.  1365. 

5  Loc.  cit.  6  Loc.  cit. 

7  Amer.  Med.,  1903,  vol.  vi,  p.  301. 


INTKST1NAL  OBSTRUCTION. 


441 


these  instances  having  been  reported  by  Leichtenstern.1  In 
bilharziasis  high  eosinophile  figures  have  also  been  reported,  for 
example,  47.6  per  cent.  (Boycott2);  33.6  per  cent.  (Russell3); 
33  per  cent,  in  one  case,  and  an  average  of  16.4  per  cent,  for 
50  cases  (Douglas  and  Hardy4);  20  per  cent.  (Coles5);  and 
18.4  per  cent.  (Balfour6).  Even  the  Oxyuris  vermicularis, 
although  it  is  not  considered  to  be  a  factor  of  anemia,  may 
cause  a  well-marked  increase  in  the  percentage  of  eosinophiles, 
these  cells  sometimes  constituting  from  10  to  15  per  cent,  of  all 
forms  of  leucocytes.  In  three  cases  of  Strongyloides  intestinalis 
infection,  reported  by  Price,7  eosinophilia  was  absent. 

Relatively  high  percentages  of  mononuclear  forms,  especially 
the  large,  and  of  basophiles  are  other  differential  changes  occa- 
sionally observed. 

XL.  INTESTINAL  OBSTRUCTION. 

The  hemoglobin  and  erythrocytes  are  unaffected,  except  in  ob- 
struction due  to  malignant  disease  or  associated  with  hemorrhage, 
in  which  there  may  be  a  moderate  secondary  anemia. 

Leucocytosis  is  a  frequent,  though  not  a  constant,  accompani- 
ment of  all  forms  of  ileus,  even  those  with  comparatively  slight 
symptoms.  The  increase  is  most  constant  in  obstruction  de- 
pending upon  malignant  disease  or  complicated  by  gangrene  and 
peritonitis,  and  in  this  class  of  cases  it  tends  to  reach  the  highest 
figures,  except  in  the  event  of  grave  intoxication.  Bloodgood8 
regards  the  presence  of  a  high  leucocytosis  (20,000  to  30,000)  on 
the  third  or  fourth  day  after  the  onset  of  symptoms  as  a  favorable 
indication  for  operative  interference,  but  he  considers  that  low 
counts  (below  10,000)  under  the  same  circumstances  indicate 
extensive  gangrene-peritonitis,  or  that  the  patient  will  be  so  de- 
pressed that  reaction  cannot  follow  relief  of  the  obstruction. 

XLI.  KALA-AZAR. 

In  many  cases  malarial  parasites  are  detected 
Parasitology,  in  the  blood  of  individuals  suffering  from  kala- 
azar,  a  finding  which  points  to  a  coincident  ma- 
larial infection.    Bentley,9  by  splenic  puncture,  demonstrated  in 

1  Cited  by  Ehrlich,  loc.  cit.  2  Brit.  Med.  Jour.,  1903,  vol.  ii,  p.  1267. 

3  Lancet,  1902,  vol.  ii,  p.  1540.  4  Ibid.,  1903,  vol.  ii,  p.  1009. 

5  Brit.  Med.  Jour.,  1902,  vol.  i,  p.  1137.  6  Lancet,  1903,  vol.  ii,  p.  1649. 

7  Jour.  Amer.  Med.,  Assoc.,  1903,  vol.  xli,  p.  651. 

8  Amer.  Med.,  1901,  vol.  i,  p.  306. 

8  Cited  by  Ross,  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  160. 


442 


GENERAL  HEMATOLOGY. 


kala-azar  the  newly  described  Leishmania  donovani,  an  observa- 
tion subsequently  confirmed  by  Rogers,1  who  found  these  bodies 
in  6  of  7  cases  of  this  disease,  as  well  as  in  15  of  30  other  febrile 
conditions  associated  with  splenomegaly  and  striking  cachexia. 
Leishman-Donovan  bodies  were  first  found  intra  vitam  by  Irish- 
man 2  in  blood  aspirated  from  the  enlarged  spleen  of  a  patient 
affected  with  so-called  "dum-dum  fever,"  and  they  were  first 
demonstrated  post-mortem  by  Donovan 3  in  smears  from  the  spleens 
in  cases  of  obscure  Indian  fevers.  Marchand  and  Ledingham4 
have  similarly  detected  these  organisms  in  a  patient  dead  of  an  ir- 
regular pyrexia,  with  anemia  and  splenomegaly,  and  Manson  and 
Low,5  Neave,6  and  Swan7  found  them  in  cases  of  tropical  spleno- 
megaly. Manson,  Low,  and  Christophers 8  detected  Leishman- 
Donovan  bodies  in  intestinal  ulcers. 

The  parasites  are  found  but  rarely  in  the  peripheral  blood, 
and  only  when  the  patient's  fever  is  high,  1030  or  1040  F. 

The  organisms  in  question  appear,  singly  and  in  clusters,  as  oval 
or  spherical  bodies,  2  or  3  p.  in  diameter,  and  consisting  of  a  limit- 


of  a  closely  related  flagellate  organism,  and  the  statements  of 
Marchand  and  Ledingham4  carry  a  similar  inference.  More 
recently  Leishman 10  pointed  out  the  resemblance  of  his  bodies 
to  the  Helcosoma  tropicum,  found  by  J.  H.  Wright11  in  the 
pus  of  that  form  of  tropical  ulcer  known  as  Delhi  sore.  It  is 
possible  that  they  are  identical  with  the  so-called  plasmodia 
found  in  Delhi  sore  by  Cunningham 12  in  1885.    Laveran13  and 

1  Cited  by  Ross,  Brit.  Med.  Journ.,  1904,  vol.  i,  p.  160. 

2  Ibid.,  1903,  vol.  i,  p.  1252.    "  3  Ibid.,  1903,  vol.  ii,  p.  79. 

4  Lancet,  1904,  vol.  i,  p.  149.  5  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  183. 

6  Ibid.,  1904,  vol.  i,  p.  1252.  1  Ibid.,  1904,  vol.  i,  p.  1487- 

8  Brit.  Med.  Jour.,  1904,  vol.  ii,  p.  11     9  hoc.  cit. 

10  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  303. 

11  Jour.  Med.  Research,  1903,  vol.  v,  p.  472. 

12  "  Scientific  Memoirs  by  Medical  Officers  of  the  Army  of  India,"  Calcutta,  1885. 

13  Bull,  de  l'Acad.  de  med.,  Paris,  1903,  vol.  1,  p.  238. 


Fig.  62. — Leishman-Donovan  Bodies. 


ing  membrane  inclosing  two  dis- 
tinct masses  of  chromatin:  one 
relatively  large  and  of  circular  or 
ring-shaped  contour,  the  other 
much  smaller,  rod-shaped,  and, 
as  a  rule,  situated  perpendicularly 
to  the  circumference  of  the  larger 
mass  (Fig.  62).  The  precise 
significance  of  these  organisms 
is  unsettled.  Leishman9  suggests 
that  they  may  be  simply  evolu- 
tion forms  of  trypanosomata  or 


KALA-AZAR. 


443 


Donovan1  believe  that  the  organisms  belong  to  the  genus  piro- 
plasma,  while  Ross2  is  strongly  inclined  to  the  view  that  they 
represent  a  novel  organism,  possibly  of  the  genus  cercomonas. 

Rogers' 3  success  in  developing  trypanosomata  from  cultures  of 
Leishman-Donovan  bodies  is  of  the  highest  importance,  if  confirmed. 

Well-defined   secondary   anemia   sooner  or 
Hemoglobin  later  develops,  due  in  part  to  the  extreme  mal- 
and         nutrition  of  the  subject  and  in  part  to  the  effect 
Erythrocytes,  of  a  coincident  ankylostomiasis,  for,  as  Bentley4 
has  shown,  this  type  of  helminthiasis  is  almost 
universally  prevalent  in  natives  stricken  with  kala-azar.   Rogers 5 
found  about  3,500,000  per  c.mm.  as  the  average  number  of  ery- 
throcytes in  his  series  of  cases.    With  the  persistence  of  such  an 
anemia  structural  changes  are  to  be  expected — poikilocytosis,  de- 
formities of  size,  polychromatophilia,  and  sometimes  a  few  normo- 
blasts. 

The  leucocyte  count  is  subnormal  in  the 
Leucocytes,  majority  of  cases,  and  extreme  leucopenia  may 
supervene.  Relative  lymphocytosis,  involving  es- 
pecially the  large  cells,  with  a  consequent  decrease  in  the  propor- 
tion of  polynuclear  neutrophiles,  is  the  general  rule.  Neave6 
found  11  per  cent,  of  small,  and  67  per  cent,  of  large,  lympho- 
cytes in  one  case.  In  10  cases  Donovan1  found  that  the  mono- 
nuclear forms  averaged  32.8  per  cent.,  of  which  23.6  per  cent, 
were  large  lymphocytes ;  and  a  still  more  decided  mononucleosis 
was  found  by  Rogers 7  in  22  cases.  Because  of  the  concomitant 
ankylostomiasis,  an  eosinophile  increase  is  common,  the  percent- 
age of  these  cells  frequently  rising  to  10  or  12.  Five  per  cent,  of 
mast  cells  were  found  in  a  case  studied  by  Swan.8 

The  blood  plaques,  according  to  Bentley,9  are  generally  very 
abundant,  even  in  the  pyrexial  stage  of  the  disease,  and  appear 
to  exhibit  multiple  areas,  staining  more  deeply  than  the  surround- 
ing body  of  the  cell. 

Hematologically,  kala-azar  closely  simulates 
Diagnosis,    malarial  fever,  save  in  two  particulars — the  ab- 
sence, in  uncomplicated  cases,  of  the  malarial 
parasite  and  of  pigment  and  the  great  increase  in  the  number  of 
plaques.    The  presence  or  absence  of  eosinophilia  is  naturally 

lancet,  1904,  vol.  ii,  p.  613. 

2  Brit.  Med.  Jour.,  1903,  vol.  ii,  p.  1261;  also  ibid.,  1904,  vol.  ii,  p.  98. 

3  Ibid.,  1904,  vol.  ii,  p.  29;  also  Lancet,  1904,  vol.  ii,  p.  215. 

4  Brit.  Med.  Jour.,  1902,  vol.  ii,  p.  872. 

5  Ibid.,  1904,  vol.  ii,  p.  647.  6  Ibid.,  1904,  vol.  i,  p.  1252. 

7  Ibid.,  1904,  vol.  ii,  p.  647. 

8  Loc.  cit.  9  Loc.  cit. 


444 


GENERAL  HEMATOLOGY. 


of  no  diagnostic  significance.  The  blood  pictures  of  kala-azar 
and  of  Malta  fever  are  very  similar,  aside  from  the  parasitology  of 
the  blood.  Although  the  blood  of  kala-azar  patients  clumps 
Bruce's  micrococcus  in  low  dilutions,  no  such  reaction  occurs  in 
high  dilutions — i  in  80  or  higher. 


XLII.  LEPROSY. 

The  studies  of  Winiarski1  and  of  P.  K.  Brown2  show  that  in 
the  early  stages  of  this  disease  neither  the  hemoglobin  nor  the 
erythrocytes  suffer  any  deterioration,  but  that  in  advanced  leprosy, 
especially  in  cases  with  extensive  ulcerative  lesions,  the  anemia 
may  be  striking — quite  as  marked,  in  fact,  as  in  a  moderately 
severe  case  of  true  Biermer's  anemia.  In  such  instances  there  is 
a  conspicuous  oligocythemia  in  comparison  to  the  oligochro- 
memia,  and  the  counts  may  fall  to  below  2,000,000  to  the  c.mm. 
A  tendency  toward  megalocytosis  and  high  color  indices  has 
been  observed,  the  index  in  some  counts  being  as  high  as  1.7. 
Normoblasts  may  occur  alone  or  in  association  with  a  few  megalo- 
blasts,  but  the  latter  never  predominate.  Polycythemia,  resulting 
from  peripheral  stagnation,  may  be  a  feature  of  some  cases.  The 
number  of  leucocytes  is  not  increased,  but  a  relative  lymphocytosis 
is  a  commonly  observed  differential  change  affecting  these  cells. 
An  eosinophilia  of  8.7  per  cent,  was  present  in  a  leper  examined 
by  Boston.3 

Brown,4  Streker,5  and  Boston6  have  succeeded  in  demon- 
strating the  Bacillus  leprce  in  the  circulating  blood  during  life. 
These  organisms,  as  a  rule,  were  found  to  be  inclosed  in  the  leuco- 
cytes, and,  more  rarely,  lay  free  in  the  plasma.  On  the  other  hand, 
Bibb7  failed  in  30  cases  to  find  the  bacillus  by  blood  culturing, 
although  he  obtained  positive  results  constantly  with  blood  as- 
pirated from  the  leprous  tubercles. 

The  serum  diagnosis  of  leprosy  has  not  yet  come  into  general 
clinical  use,  although  positive  clump  reactions  with  cultures  of 
the  leprosy  bacillus  and  the  serum  of  lepers  have  been  observed. 

1  St.  Petersburg  med.  Wochenschr.,  1892,  vol.  ix,  p.  365. 

2  Trans.  California  State  Med.  Soc.,  1897,  vol.  xxvii,  p.  168. 

3  Proc.  Phila.  Co.  Med.  Soc.,  1903,  vol.  xxiv,  p.  6. 

4  Loc.  cit.  5  Miinch.  med.  Wochenschr.,  1897,  vol.  xliv,  p.  1103. 
6  Loc.  cit.  7  Amer.  Jour.  Med.  Sci.,  1894,  vol.  cviii,  p.  539. 


MALARIAL  FEVER. 


445 


XLIII.  MALARIAL  FEVER. 

The  specific  cause  of  malarial  fever  is  a  form 
Parasitology,  of  blood  parasite  generally  known  as  the  Plas- 
modium malarice  or  the  Hcemamceba  malaria,  an 
organism  classified  among  the  Sporozoa,  according  to  Metschni- 
koff.1  First  accurately  described  in  1880  by  Laveran,2  a  medical 
officer  of  the  French  army  stationed  in  Algeria,  our  knowledge 
of  the  parasite  and  its  relation  to  the  malarial  fevers  have  been 
furthered  chiefly  by  the  researches  of  Richard,3  also  a  French 
army  surgeon;  of  Grassi  and  Filetti,4  in  Sicily;  of  Mannaberg,5 
in  Austria;  of  Marchiafava  and  Celli,6  Bastianelli  and  Bignami,7 
and  Golgi,8  of  the  Italian  school;  of  Manson9  and  Ross,10  in 
England  ;  and  of  Councilman  and  Abbott,11  Sternberg,12  Osier,13 
Dock,14  Thayer  and  Hewetson,15  and  Craig,16  in  America.  In 
addition  to  these  principal  investigators,  numerous  workers  in 
other  parts  of  the  world  have  materially  advanced  our  knowledge 
of  the  subject.17 

Developmental  Cycle  in  Man. — The  malarial  organism  gains 
entrance  to  the  erythrocyte  of  man,  in  which  it  pursues  a  definite 
cycle  of  development  at  the  expense  of  its  corpuscular  host. 
Existing  in  its  earliest  stages  as  a  hyaline,  ameboid  body  within 
the  substance  of  the  corpuscle,  the  parasite  increases  in  size,  and 

1  Centralbl.  f.  Bakt.  u.  Parasit.,  1887,  vol.  i,  p.  624. 

2  "Nature  parasitaire  des  accidents  de  l'impaludisme,"  Paris,  1881. 

3  Gaz.  med.  d.  Paris,  1882,  vol.  iv,  p.  252. 

4  Centralbl.  f.  Bakt.  u.  Parasit.,  1890,  vol.  vii,  pp.  396  and  430;  ibid.,  1891 
vol.  ix,  pp.  403,  429,  and  461;  ibid.,  1891,  vol.  x,  p.  449. 

5  "The  Malarial  Parasites,"  New  Sydenham  Soc.  Trans.,  London,  1894,  vol. 
cl,  p.  241. 

6  Fortsch.  d.  Med.,  1885,  vol.  hi,  p.  787;  ibid.,  1888,  vol.  vi,  p.  450;  also 
Festschr.  z.  Virchow's  70.  Geburtstag,  1891,  vol.  hi,  p.  187. 

7Riforma  med.,  1890,  vol.  vi,  pp.  860,  866,  and  872;  also  Lancet,  1898,  vol. 
ii,  p.  1461. 

8  Arch,  per  le  sc.  med.,  1886,  vol.  x,  p.  109. 

9  Lancet,  1896,  vol.  L  pp.  695,  751,  and  831;  also  Brit.  Med.  Jour.,  1894, 
vol.  ii,  p.  1306. 

10  "Report  on  the  Cultivation  of  Proteosoma  (Labbe)  in  Gray  Mosquitoes," 
Calcutta,  1898. 

11  Amer.  Jour.  Med.  Sci.,  1885,  vol.  lxxxix,  p.  416;  also  Med.  News,  1887, 
vol.  i,  p.  59. 

12  Med.  Record,  1886,  vol.  xxix,  pp.  489  and  517. 

13  Phila.  Med.  Times,  1886,  vol.  xvii,  p.  126. 

14  Med.  News,  1890,  vol.  lvii,  p.  59;  ibid.,  1891,  vol.  lviii,  pp.  602  and  628. 

15  Johns  Hopkins  Hosp.  Reports,  1895,  vol.  v,  p.  3. 

16  "  Estivo-autumnal  Malarial  Fevers,"  New  York,  1901. 

17  For  an  exhaustive  bibliography  the  reader  should  consult  Thayer's  admirable 
monograph,  "Lectures  on  the  Malarial  Fevers,"  New  York,  1897.  An  authorita- 
tive account  of  the  malarial  fevers  in  all  their  phases  is  given  in  Celli's  book, 
"Malaria  According  to  the  New  Researches,"  English  translation  by  J.  J.  Eyre, 
London  and  New  York,  1900.  The  estivo-autumnal  fevers  are  well  dealt  with  in 
Craig's  book  above  noted. 


446 


GENERAL  HEMATOLOGY. 


derives  fine  pigment  granules  from  the  hemoglobin  of  its  host, 
which  it  ultimately  destroys  at  the  time  its  full  maturity  is  attained. 
Full  development  of  the  parasite  having  been  reached,  it  divides 
into  a  number  of  segments,  which,  by  the  rupture  of  the  blood 
cell,  are  set  free  to  enter  fresh,  uninvaded  erythrocytes  and  there 
to  initiate  a  new  developmental  cycle  of  similar  characteristics. 
Segmentation  or  sporulation  of  a  group  of  parasites  is  accompa- 
nied by  a  paroxysm,  which  in  all  probability  is  due  to  the  influence 
of  certain  toxic  material  liberated  at  this  time. 

The  favorable  effect  of  quinin  in  malaria  King1  attributes  to 
the  fluorescence  of  the  drug,  whereby  violet  rays  flood  the  blood 
and  thus  deprive  the  parasites  of  the  light  requisite  for  their 
sporulation.  This  ingenious  theory  is  based  upon  the  fact  that 
light  is  essential  for  fluorescence,  and  upon  the  hypothesis  that 
the  malarial  pardsite  must  have  light  in  order  to  segment.  It 
explains  why  quinin  cures  the  paroxysms  of  tertian  and  quartan 
fevers,  and  also  why  it  fails  materially  to  influence  those  due  to 
estivo-autumnal  crescents.  In  the  first  two  infections  the  organ- 
isms circulate  freely  in  the  peripheral  blood,  where  there  is  enough 
light  to  develop  fluorescence,  while  in  the  latter  the  organisms  are 
largely  confined  to  the  deep  circulation,  where,  because  of  dark- 
ness, no  fluorescence  occurs.  In  addition  to  quinin,  fraxin  and 
aesculin  possess  fluorescent  properties  and  are  also  therapeutically 
active  in  paludism. 

In  order  to  complete  its  full  life  cycle,  the  malarial  parasite 
must  also  pass  through  a  developmental  phase  within  the  bodies 
of  certain  mosquitos,  for  it  has  been  shown  that  these  insects  not 
only  act  as  the  intermediate  hosts  of  the  parasite,  but  also  carry 
the  infection  by  means  of  their  bite.  These  important  discoveries 
were  first  made  by  Ross,2  whose  conclusions  were  shortly  con- 
firmed by  Grassi,  Bignami,  Bastianelli,3  and  by  others  of  the 
Italian  school. 

Developmental  Cycle  in  the  Mosquito. — While  in  the  human 
body  the  malarial  parasite  pursues  an  asexual  cycle,  terminating 
in  segmentation,  in  the  body  of  mosquitos  of  the  genus  Anopheles 
it  follows  out  a  true  sexual  cycle.  In  the  blood  of  man  certain 
of  the  parasites  which  do  not  undergo  segmentation  constitute 
sexual  forms  of  the  organism,  known  as  gametes,  which,  after 
having  been  imbibed  by  the  mosquito  while  biting  a  malarious 

1  Amer.  Jour.  Med.  Sci.,  1902,  vol.  exxiii,  p.  1025. 

2  Loc.  cit. 

3  Reale  Accademia  dei  Lincei.  Estratto  dal,  vol.  vii,  20  sem.,  ser.  5a.,  fasc.  ri°, 
Seduta  del  4  dicembre,  1898;  abst.  in  Progressive  Med.,  Philadelphia,  1899,  vol. 
i,  p.  287;  also  Bignami,  Lancet,  189S,  vol.  ii,  pp.  1461  and  1541;  also  Grassi,  II 
Policlinico.  1898,  vol.  v,  p.  469. 


- 


CHART  III 

SINGLE  TERTIAN  INFECTION. 
Paroxysm  every  third  clay. 
P.  P.  P.  P.  P.  P.  P. 

*<*###** 

/  V  v  v  v  v  v  

Day.    1         2        3        4       5        0        7         8       9        10      11       12  13 


DOUBLE  TERTIAN  INFECTION. 
Daily  paroxysm. 
P.       P.       P.       P.       P.       P.       P.       P.       P.  P. 


3        4        5         0       7        8       9       10      11  12 


SINGLE  QUARTAN  INFECTION. 

Paroxysm  every  fourth  day. 
P.  P.  P. 


■V  v  v  ^ 

4       5        0        7        8        9       10      11      12  13 


DOUBLE  QUARTAN  INFECTION. 
Paroxysm  on  two  successive  days  with  one  day's  intermission. 

P.      P.  P.       P.  P.       P.  P.       P.  P.  P. 

*       *  *        *  *        *  **  *  * 

/ — /  v— V=  v    V     =V~A/  ^=V= 

Day.   1        2        3       4        5        0        7        8        9       10       11       12  13  14 


TRIPLE  QUARTAN  INFECTION. 
Daily  paroxysm. 

P.      P.      P.       P.       P.       P.      P.       P.      P.      P.      P.  P. 

**        **        *        *****  ** 


2        3       4        5        0       7        8        9       10      11  12 

CHART  ILLUSTRATING  THE  DIFFERENT  TYPES  OF  FEVER 
RESULTING  FROM  INFECTION  WITH  SINGLE  AND  WITH 
MULTIPLE  GROUPS  OF  MALARIAL  PARASITES. 

The  duration  of  the  parasites'  cycle  of  development 
is  expressed  by  colored  lines,  thus: 
Black:  First    group  of  parasites. 
Red:     Second    "       "      "  " 
Blue:    Third      "       "      "  " 
P:  Paroxysm. 


MALARIAL  FEVER. 


447 


individual,  develop  into  impregnated  bodies  by  reason  of  the 
fecundation  of  the  female  sexual  elements,  or  macro  gametes,  by  the 
free  flagella,  or  microgametes,  which  have  become  detached  from 
the  male  sexual  elements,  or  micro gamelocytes.  The  resultant 
fertilized  bodies  develop  into  motile  pseudo-vermicules,  which, 
having  penetrated  the  muscular  wall  of  the  mosquito's  stomach, 
lodge  and  become  encysted  in  this  situation  and  are  now  known 
as  zygotes.  From  the  latter  are  derived  large  numbers  of  delicate 
spindle-shaped  cells,  or  sporoblasts,  which,  by  the  rupture  of  the 
zygote's  capsule,  are  set  free,  and,  as  sporozoids,  make  their  way 
into  the  salivary  gland  of  their  host,  whence  they  pass  by  way  of 
the  salivary  duct  into  the  proboscis  of  the  insect,  and  consequently 
into  the  circulating  blood  of  the  individual  stung  by  the  infected 
mosquito.  The  sporozoids  thus  inoculated  into  the  blood  of  man 
penetrate  his  erythrocytes,  in  which,  as  the  young  hyaline  forms 
of  the  malarial  parasite,  they  pursue  the  typical  developmental 
cycle  to  be  described  below. 

Thus,  it  has  been  definitely  shown  that  mosquitos  of  the  genus 
Anopheles  are  capable  of  transmitting  malarial  infection  from  man 
to  man,  and  it  is  now  generally  believed  that  this,  the  only  proved 
method  of  malaria  transmission,  is  probably  the  sole  means  by 
which  the  disease  is  spread.  The  ordinary  house-mosquito,  of 
the  genus  Culex,  is  not  concerned  in  the  transmission  of  malaria, 
since  it  has  been  shown  that  the  parasites  do  not  follow  out  a 
developmental  cycle  within  the  body  of  this  insect. 

For  a  complete  review  of  the  " mosquito  theory"  of  malaria, 
embracing  the  work  of  Ross,  Manson,  MacCallum,  and  the 
Italian  school,  the  reader  should  consult  Thayer's  "  Recent 
Advances  in  our  Knowledge  Concerning  the  Etiology  of  Malarial 
Fever,"1  Futcher's  "A  Critical  Summary  of  Recent  Literature 
Concerning  the  Mosquito  as  an  Agent  in  the  Transmission  of 
Malaria,"  2  and  Howard's  "Mosquitoes." 

Varieties  of  the  Malarial  Parasite. — Three  distinct  varieties  of 
the  parasite  are  recognized,  each  of  which  has  been  found  con- 
stantly associated  with  a  specific  type  of  malarial  infection.  These 
three  varieties  are : 

1.  The  parasite  of  tertian  fever,  associated  with  a  regularly 
intermittent  type  of  fever,  with  paroxysms  every  third  day. 

2.  The  parasite  of  quartan  fever,  associated  with  a  regularly 
intermittent  type  of  fever,  with  paroxysms  every  fourth  day. 

3.  The  parasite  of  estivo- autumnal  fever,  associated  with  the 
more  irregular  types  of  fever. 

1  Proc.  Phila.  Co.  Med.  Soc,  1900,  vol.  xxi,  p.  211. 

2  Amer.  Jour.  Med.  Sci.,  1899,  vol.  cxviii,  p.  318. 


448 


GENERAL  HEMATOLOGY. 


The  parasites  of  tertian  and  of  quartan  fever  exist  in  the  blood 
of  the  infected  individual  in  great  groups,  consisting  of  immense 
numbers  of  organisms,  all  of  which  are  approximately  at  the  same 
stage  of  development,  and  therefore  undergo  sporulation  at  about 
the  same  period.  This  fact  serves  to  explain  the  regularity  of 
the  tertian  and  quartan  paroxysms.  On  the  other  hand,  in  estivo- 
autumnal  infections  this  regular  grouping  of  the  parasites  is  often 
wanting,  and  large  numbers  of  this  organism  commonly  exist  in 
the  blood  in  different  stages  of  development.  Sporulation  thus 
taking  place  at  irregular  intervals,  irregularity  in  the  occurrence 
of  the  estivo- autumnal  paroxysms  is  extremely  common. 

As  the  development  of  these  three  types  of  the  malarial  parasite 
progresses,  certain  forms  are  evolved  which  possess  more  or  less 
common  characteristics,  so  that  it  is  convenient  to  speak  of  these 
forms,  which '  represent  the  maturing  phases  of  the  organism,  as 
follows : 

(a)  The  intracellular  hyaline  forms. 

(b)  The  intracellular  pigmented  forms. 

(c)  The  extracellular  pigmented  forms. 

(d)  The  segmenting  forms. 

(e)  The  flagellate  forms. 

Furthermore,  in  parasites  of  the  estivo-autumnal  type  addi- 
tional forms — those  of  the  crescent  group — are  met  with,  these 
varieties  being  peculiar  to  this  type  of  infection  and  never  occurring 
in  tertian  and  quartan  fevers. 

Tertian  infections  constitute  the  prevailing  type  of  malarial 
fever  in  almost  all  countries  in  which  the  disease  exists.  Quartan 
fevers  are  relatively  uncommon,  except  in  certain  limited  districts 
— parts  of  Sicily,  for  example  ? — in  which  a  large  proportion  of  the 
cases  conform  to  this  type.  Estivo-autumnal  fevers  are  especially 
common  in  the  tropics,  but  this  type  of  the  disease  is  by  no  means 
incompatible  with  temperate  regions.  In  Philadelphia  and  its 
environs  tertian  infections  are  about  five  times  as  common  as  those 
of  the  estivo-autumnal  type,  while  quartan  malaria  is  practically 
unknown.  The  writer  has  seen  but  a  single  instance  of  quartan 
infection  in  this  vicinity,  and  this  case  was  without  doubt  imported. 

The  Parasite  of  Tertian  Fever  (Plate  VI). — The  tertian  parasite 
attains  its  full  development  in  about  forty-eight  hours,  segmenta- 
tion of  a  single  group  of  organisms  at  this  interval  producing  the 
characteristic  paroxysms  every  third  day.  Infection  with  two  dis- 
tinct groups  of  parasites,  each  maturing  on  successive  days,  gives 
rise  to  a  quotidian  type  of  fever,  characterized  by  the  occurrence  of 
daily  paroxysms.    (See  Chart  III,  p.  447.)    Infection  with  more 


PLATE  VI, 


@  ®  ®  @  ©  © 

1  2  3  4  5  6 


8 


10  11 


12 


14 


P 
15    /  i 


The  Tertian  Parasite. 


1.  Normal  erythrocyte. 

2,  3,  4,  5.  Intracellular  hyaline  forms. 

6,  7.  Young  pigmented  intracellular  forms.  In  6  two  distinct  parasites  inhabit  the  ery- 
throcyte, the  larger  one  being  actively  ameboid,  as  evidenced  by  the  long  tentacular 
process  trailing  from  the  main  body  of  the  organism.  This  ameboid  tendency  is 
still  better  illustrated  in  7,  by  the  ribbon-like  design  formed  by  the  parasite.  Note 
the  delicacy  of  the  pigment  granules,  and  their  tendency  toward  peripheral  arrange- 
ment in  6,  7,  and  8. 

8.  Later  developmental  stage  of  7.    In  7,  8,  and  9  enlargement  and  pallor  of  the  infected 

erythrocyte  become  conspicuous. 

9.  Mature  intracellular  pigmented  parasite. 

10.  11,  12.  Segmenting  forms.    In  10  is  shown  the  early  stage  of  sporulation — the  develop- 

ment of  radial  striations  and  peripheral  indentations  coincidentally  with  the  swarm- 
ing of  the  pigment  toward  the  center  of  the  parasite.  The  completion  of  this  process 
is  illustrated  bv  11  and  12. 

13.  Large  swollen  extracellular  form.     Note  the  coarse  fused  blocks  of  pigment.  (Com- 

pare size  with  that  of  normal  erythrocyte,  1.) 

14.  Flagellate  form. 

15.  Shrunken  and  fragmenting  extracellular  forms. 

16.  Vacuolation  of  an  extracellular  form. 

Note. — The  original  water-color  drawings  were  made  from  fresh  blood  specimens,  a 
Leitz  xVinch  oil-immersion  objective  and  4  ocular,  with  a  Zeiss  camera-lucida,  being  used. 


(E.  F.  Faber,/<?c.) 


MALARIAL  FEVER.  449 

than  two  groups  is  extremely  rare,  and  produces  an  atypical  and 
irregular  type  of  fever. 

Anticipation  of  the  paroxysm,  which  is  especially  frequent  in 
tertian  fever,  may  be  explained  by  a  precocity  displayed  by  a 
group  of  parasites,  by  virtue  of  which  their  development  is  so 
rapid  that  the  stage  of  sporulation  is  reached  before  the  expira- 
tion of  forty-eight  hours.  On  the  contrary,  should  the  develop- 
ment of  a  group  happen  to  be  slower,  requiring  more  than  forty- 
eight  hours  for  its  full  maturity  and  sporulation,  then  the  paroxysm 
is  retarded. 

If  a  specimen  of  fresh,  unstained  blood  from  a  case  of  tertian 
fever  is  examined  during  the  period  immediately  or  shortly  fol- 
lowing the  malarial  paroxysm,  it  will  be  observed  that  many  of 
the  erythrocytes  contain  small,  pale,  transparent  foreign  bodies, 
dim  of  outline,  more  or  less  markedly  ameboid  in  character,  and 
of  a  peculiar  dirty,  grayish-pearl  tint.  These  bodies,  known  as 
the  intracellular  hyaline  forms,  or  amebulcB,  represent  the  youngest 
forms  of  this  organism,  being  derived  from  the  sporulation  of  the 
immediately  preceding  group  of  parasites.  They  may  occasionally 
be  found  m  the  peripheral  blood  toward  the  latter  part  of  the 
paroxysm,  and  for  a  short  time  after  the  occurrence  of  this 
phenomenon.  , 

The  ameboid  movements  of  these  hyaline  bodies  form  one  of 
their  most  striking  features,  and  in  consequence  of  this  trait  their 
shape  is  constantly  altered.    At  one  moment  the  parasite  appears 
as  a  flattened  spherical  or  oval  disc,  measuring  2  or  3  ju  in  diameter; 
the  next  instant  it  may  change  to  the  shape  of  a  jack-stone,  or 
become  a  stellate  design  or  take  the  form  of  an  anvil.    The  suc- 
cession of  figures  which  the  organism  may  resemble  is  limitless. 
As  the  parasite  increases  in  size  long  pseudopodia,  like  the  delicate 
tendrils  of  a  vine,  are  alternately  thrown  out  and  retracted,  reaching 
here  and  there  through  the  corpuscular  substance  with  uncertain 
but  sudden  motility.    In  the  active  parasite  these  pseudopodia 
appear  as  long,  delicate,  gracefully  curved  branchings  of  the  pro- 
toplasm, usually  terminating  in  a  spherical,  knob-like  extremity, 
and  measuring  4  or  5  fi  in  length  in  many  instances.  Occasionally 
the  parasite  seems  to  have  formed  a  perfect  ring,  either  because 
of  the  thinning  out  of  its  central  portion,  or,  rarely,  by  reason- 
of  the  fusion  of  two  short  pseudopodia  between  which  a  small 
portion  of  the  corpuscle  becomes  imprisoned.    The  outline  and 
color  of  the  hyaline  body  are  quite  characteristic,  at  least  to  the 
eye  of  the  practised  observer.    Usually  described  as  quite  color- 
less, the  parasite  rather  possesses  a  distinctive  pearly  tint,  overlaid 
m  patches  by  strata  of  corpuscular  substance  of  varying  depth, 


450  GENERAL  HEMATOLOGY. 

so  that  in  certain  lights  the  yellowish-green  color  of  the  erythrocyte 
predominates  and  obscures  the  true  color  of  the  organism  to  some 
extent.  Usually  but  a  single  hyaline  body,  situated  somewhat 
eccentrically,  is  found  in  the  corpuscle;  less  commonly,  two  or 
more  are  harbored.  . 

The  next  stage  in  the  development  of  the  organism,  the  col- 
lection of  pigment  granules  derived  from  the  hemoglobin  of  the 
erythrocyte,  is  reached  toward  the  latter  part  of  the  first  twenty- 
four  hours  following  the  paroxysm.  By  this  time  the  size  of  the 
parasite  has  increased  to  about  half  that  of  its  corpuscular  host, 
and  it  is  now  known  as  an  intracellular  pigmented  form. 

The  pigment  appears  as  a  collection  of  exceedingly  fine,  yel- 
lowish-brown granules,  which  are  usually  most  densely  distributed 
near  the  peripheral  rather  than  the  central  portion  of  the>  parasite. 
In  the  large  spherical  forms  of  the  latter  most  of  the  pigment  is 
arranged  in  a  series  of  irregular  clumps,  loosely  _  strung  together 
by  delicate,  wavy  connecting  lines  consisting  of  individual  gran- 
ules- or  the  rim  of  the  parasite  may  be  paralleled  for  the  greater 
part' of  its  extent  by  a  pigment  design  not  unlike  a  wreath  or  a 
hoop.  The  individual  granules  are  observed  to  be  in  active,  in- 
cessant motion,  their  violent  oscillations  hither  and  thither  form- 
ing a  picture  that  at  once  arrests  the  attention  of  the  observer.  # 

In  many  of  the  ameboid  figures  a  polar  distribution  of  the  pig- 
ment is  noticeable,  the  greater  part  of  the  granules  being  situated, 
in  fine  clumps,  in  the  knob-like  extremities  of  the  several  pseudo- 
podia;  and  even  in  these  situations  the  typical  tendency  of  the 
pigment  to  arrange  itself  eccentrically  is  striking. 

As  the  parasite  matures  it  becomes  of  still  larger  size,  more 
and  more  pigmented  and  less  and  less  ameboid,  the  latter  char- 
acteristic becoming  quite  or  almost  entirely  lost  by  the  time  it 
attains  its  full  growth.  The  pigment,  fine  of  yellowish-brown 
color,  and  eccentrically  distributed  in  the  earlier  forms,  is  at  this 
period  of  the  organism's  growth  much  coarser,  darker  m  color, 
and  more  scattered  throughout  the  protoplasm.  Some  ot  trie 
granules  are  fused  into  minute,  dark-colored  spikes  and  rods  m 
contrast  to  the  discrete,  dot-like  granules  of  the  younger  parasites. 

Coincidentally  with  these  changes  striking  alterations  are  ap- 
parent in  the  invaded  erythrocytes.  These  cells  become  pro- 
gressively paler  and  more  swollen  as  the  development  of  the  para- 
ge goes  on,  until  at  the  time  of  the  latter's  full  maturity  (attained 
after  a  growth  of  about  forty  hours'  duration)  the  corpuscles  have 
become  almost  entirely  decolorized,  and  appear  now  as  hyaline 
or  pale  yellowish  rims  encircling  the  parasite,  the  size  of  which  is 
now  approximately  equal  to  that  of  a  normal  erythrocyte. 


MALARIAL  FEVER.  ^ 

to  fortv  It'?'11'  ^f8  !hC  nCXt  ^oxysm,  or  from  about  forty 
ts  6"SlT         the  Precerding  chiI1>  the  P«asite  attains 
lnta  7  alKl  the  Stage  0f  sP°™lation  occurs.  Coinci- 

dentally  with  this,  segmenting  jorms  of  the  parasite,  also  known 
as  sporocy  es,  begin  to  appear  in  the  blood.  In  tertian  infeXns 
segmentation  occurs  to  a  greater  extent  in  the  d  ep  Sian  in  the 
peripheral  circulation,  but  if  finger  blood  is  obtained  two  or  &  ee 
found  if  7  w'  "  I6"  "inters"  will  almost  always  be 
i  ^  search  is  careful  and  thorough.    In  cases 

in  which  the  number  of  parasites  has  been  scanty  during  the  pre 
ceding  days  of  the  attack  it  may  be  impossible  to  defect  these 
forms  in  spite  of  careful,  skilled  observation 

Segmentation  is  heralded  by  a  tendency  of  the  pigment  gran- 
ts to  collect  m  or  near  the  center  of  the  parasite  in  one  large 
or  in  several  smaller  compact  clumps  or  fused  masses  This 
having  taken  place,  a  number  of  minute,  somewhat  refractive 
points  may  be  seen  with  more  or  less  distinctness,  the  majo  fiy 
of  these  spots  being  confined  to  the  peripheral  portion  of  21 

ZrnT™,WhiCh  ^  ^  time  ^  l0St  "  ^dearo  Ts  e  rhe 
clear,  hyaline  appearance,  and  has  become  dully  opaoue  and 
somewhat  granular.    Following  the  development  oi  thesfrefrac 
five  points,  indistinct  parallel  linear  shadings,  usuallylftS^ 
twenty  in  number,  extending  from  the  periphery  of  the  parasite 
toward  the  central  collection  of  pigment,  may  be  discerned  and 

wrinkled111^  I*- tWf  Change  *°  rim  of  the  parashe  blmls 
pa  r  nf  t'h     n  ™™g^d>  each  corrugation  capping  a 

pair  of  these  radiating  shadings.  The  latter  finally  become  fhe 
-t-nty  apores  or  segmentsfof  ^/whS 
round  or  ovoid  shape,  radiating  m  an  irregular  figure  toward  the 
central  pigment  mass.  By  careful  focusing  each  segment! found 
to  contain  a  central  refractive  spot,  the  whole  collect^ I  bZs 
urrounded  and  held  together  by  the  shell  of  the  erythrocyte  now 
so  decolorized  that  it  is  scarcely  visible. 

Finally,  when  segmentation  is  completed,  the  spores-for  as 
such  these  segmenting  bodies  must  now  be  considered-are  freed 
rom  the  body  of  the  corpuscle  which  has  served  until  this  time 
as  their  limiting  capsule.    The  latter  having  apparent  y  ruptured 

dther  *  emergin^everafat  f 

number    The   n         \nd  ^emery  abrupt  exit  of  their  whole 
number     I  he  spores,  which  now  lie  free  in  the  blood  nlasms 

^whichh^  ?V\CM  ma^  in  an  irregul; 

group  which  has  been  likened  in  appearance  to  a  bunch  of  Wane, 
Sooner  or  later  they  wander  off  through  the  plasma  and  d  s  iXr 
from  view,  the  inference  being  that  they  invade  fresh  erythrocytes 


4^2  GENERAL  HEMATOLOGY. 

and  thus  initiate  a  new  cycle  of  development  of  another  forty- 
eight  hours'  duration.  Although  visual  proof  of  this  invasion  is 
lacking,  the  fact  that  hyaline  bodies,  biologically  similar  to  these 
free  spores,  are  found  in  the  erythrocytes  at  or  shortly  after  the 
time  of  segmentation,  must  be  regarded  as  sufficiently  strong 
evidence  of  the  truth  of  this  inference.1  Most  of  the  liberated 
pigment  is  carried  off  through  the  blood,  to  be  deposited  m  various 
organs,  while  some  of  it  is  taken  up  by  phagocytes.  These  cells 
probably  also  engulf  any  free  spores  which  fail  to  penetrate  the 
erythrocytes.  .  . 

The  preceding  remarks  refer  to  the  typical  circle  of  the  par- 
asite's development,  from  the  smallest  hyaline  intracellular  body 
to  the  full-grown  pigmented  segmenting  variety,  from  which  the 
former  is  derived.  But  all  the  parasites  of  one  group  do  not 
pursue  this  routine,  some  escaping  prematurely  from  the  eryth- 
rocyte at  an  early  period  of  their  life  history,  others  continuing 
to  develop  further,  and  losing  their  corpuscular  capsule  just  prior 
to  the  time  segmentation  begins  in  the  other  parasites  of  the 
same  group.  In  consequence  of  the  latter  change  another  distinct 
class  of  tertian  parasites,  the  extracellular  pigmented  forms,  or 
gametes,  is  produced,  and  it  is  the  varieties  of  this  class  that  we 
now  have  to  consider.  > 

In  the  first  instance,  the  young,  slightly  pigmented  parasite 
escapes  from  its  corpuscular  host  through  an  apparent  breach  m 
the  surface  of  the  latter.  The  immediate  effect  of  its  contact 
with  the  blood  plasma  is  to  convert  it  into  a  deformed,  dwarted 
body  of  protoplasm,  which  sooner  or  later  becomes  wholly  devoid 
of  ameboid  motion.  It  is  often  fragmented  and  divided  into  two 
or  more  small  rounded  masses,  each  containing  an  amount  ot 
pigment  seemingly  disproportionate  to  its  size,  compared  to  the 
quantity  found  in  the  intracellular  forms.  Sometimes  two  of  these 
pigmented  spheres  are  joined  to  each  other  by  a  filmy  connecting 
thread  of  protoplasm,  from  3  to  5  V-  in  length,  forming  a  design 
which  may  be  compared  to  a  miniature  cham-shot.  Alter  trie 
lapse  of  a  short  length  of  time  the  outlines  of  these  bastard  torms 
of  the  parasite  become  almost  indistinguishable.  The  erythrocytes 
from  which  they  have  escaped  become  completely  decolorized  and 
invisible  shortly  after  this  accident  has  occurred. 

In  the  second  instance,  in  which  the  parasite  loses  its  corpus- 
cular envelop  just  before  the  time  of  segmentation,  the  resulting 
spherical  extracellular  body  is  usually  of  large  size,  often  9  to 

1  Christy's  drawings  (Brit.  Med.  Jour,  1903,  vol.  ii,  p.  645),  showing  free 
hyaline  orgAmZdLLg  to  and  apparently  entering  the  erythrocytes,  are  of 
Interest  in  connection  with  this  question. 


MALARIAL  FEVER.  ^ 

12  fx  m  its  greatest  diameter,  or,  in  the  smaller  forms,  about 
the  size  of  the  normal  erythrocyte.  It  is  filled  with  actively 
moving  pigment  granules,  wreathed  in  the  center  of  the  parasite 
arranged  peripherally,  or  scattered  throughout  its  body,  and 
standing  out  m  bold  relief •  against  the  background  formed  by  the 
pale  surface  of  the  parasite.  The  granules  in  this  form  of  the 
organism  are  usually  quite  dark  in  color,  some  of  them  being 
welded  and  fused  into  minute  spiculate  figures,  while  others  remain 
tree  and  distinct.  As  a  rule,  male  gametes  contain  pigment  in 
the  lorm  of  a  more  or  less  compact  central  mass,  while  in  female 
gametes  the  pigment  is  arranged  in  the  form  of  a  loose  loop  or 
wreath  m  the  center  of  the  organism. 

These  extracellular  pigmented  bodies  are  of  especial  interest 
for  the  reason  that  from  them  develop  those  most  striking  varieties 
of  the  malarial  parasite,  the  flagellate  forms.    The  earliest  evidence 
of  the  process  of  flagellation  is  seen  in  the  strikingly  increased 
activity  of  the  pigment,  the  oscillations  of  the  granules  growing 
more  and  more  violent  with  the  approach  of  the  phenomenon 
inen  one  or  more  long,  almost  transparent  tentacular  processes 
are  observed  suddenly  to  burst  from  the  periphery  of  the  parasite, 
their  violent  and  incessant  whipping  about  in  the  plasma  causing 
more  or  less  disturbance  of  the  blood  corpuscles  in  their  vicinity 
ine  pigment  granules,  meanwhile,  have  swarmed  together  into  a 
loose  mass  at  or  near  the  center  of  the  main  body.    The  length  of 
the  flagella  varies  from  4  to  5  to  20/.  or  longer,  their  average 
breadth  being  somewhat  less  than  0.5       They  frequently  possess 
one  or  more  bulbous  swellings,  usually  at  their  distal  extremity 
occasionally  at  their  proximal  end,  and  also  at  other  points  alona 
their  course  intermediate  to  these  situations.    They  may  or  mav 
not  contain  a  few  fine  and  active  dotlets  of  pigment  situated  in 
the  swollen  extremity,  or  sprinkled  as  fine  stipplings  along  their 
course.  5 

The  ultimate  disposition  of  the  flagella  occurs  in  one  of  two 
ways:   they  either  become  detached  from  the  large  spherical 

propelled  by  their  own  ameboid  movements,  which  finally  cease 
after  which  they  soon  disappear  from  view;  or,  remaining  attached 

1^1  krg"  b°fy'  they  are  observed  to  disappear  by  apparently 
reentering  the  large  parasite  and  becoming  reincorporated  with 
its  protoplasm.  Flagellate  forms  do  not  occur  in  the  circulating 
blood,  and  are  not  found  in  the  fresh  specimen  until  some  little 
tame  usually  from  ten  to  twenty  minutes,  has  elapsed  after  the 
withdraws  of  the  Mood  from  the  body  They  are  most  easily 
found  m  blood  which  has  been  taken  from  the  patient  just  before 


GENERAL  HEMATOLOGY. 

the  Onset  of  a  paroxysm.  The  nature  and  functions  of  these 
flagellate  bodies  were  first  clearly  determined  by  MacCallum,1 
who  proved  that  the  flagella  are  true  male  sexual  organs,  actively 
concerned  in  the  process  of  fertilization,  to  which  reference  has 
already  been  made.  (See  p.  446-)  The  parasites  from  which 
they  develop  are  obviously  male  gamete  forms,  or  microgameto- 
cytes. 

Some  of  the  gamete  forms,  failing  to  develop  flagella,  undergo 
vacuolization,  often  become  exceedingly  misshapen,  and  sometimes 
fragmented,  these  changes  being  regarded  as  degenerative  in 
character.  A  parasite  thus  affected  loses  its  regularly  spherical 
outline,  and  mav  so  alter  in  appearance  that  it  resembles  a  gourd 
or  a  partly  inflated  balloon.  Constrictions  at  one  or  more  points 
may  appear,  and  in  the  little  knobs  thus  cut  off  from  the  main 
body  of  the  organism  a  few  actively  motile  pigment  granules  are 
usually  imprisoned.  Small  portions  of  the  original  body,  contain- 
ing active  pigment,  may  become  extruded  and  float  off  through 
the  plasma,  but  sooner  or  later  the  pigment  in  these  fragmented 
bits  loses  its  motility  and  the  bodies  themselves  become  deformed 
and  so  indistinct  of  outline  that  they  are  lost  to  view.  These 
degenerative  forms  closely  resemble  those  derived  from  prema- 
turely escaped  intracellular  parasites,  except  that  the  latter,  as 
a  rule,  contain  finer  and  less  abundant  pigment. 

2.  The  Parasite  of  Quartan  Fever  (Plate  VII). — The  quartan 
parasite  completes  its  cycle  of  development  in  about  seventy-two 
hours,  thus  producing  a  paroxysm  every  fourth  day.  Infection 
with  two  separate  groups  of  parasites  is  marked  clinically  by  a 
paroxysm  occurring  on  each  of  two  successive  days,  separated  by 
one  day  of  intermission.  Infection  with  three  groups  of  parasites 
produces  daily  paroxysms,  the  resulting  quotidian  type  of  fever 
being  similar  to  that  due  to  double  tertian  infections.  (See  Chart 
III,  p.  447-) 

Ordinarily,  the  quartan  parasite's  cycle  of  development  is  ex- 
tremely regular,  the  period  required  for  its  maturation  seldom 
deviating  from  seventy-two  hours.  It  is  owing  to  this  that  antici- 
pation and  retardation  of  the  paroxysm,  so  common  in  tertian 
infections,  are  rare  in  the  quartan  types  of  fever. 

The  young  hyaline  forms  of  the  quartan  parasite  closely  re- 
semble those  of  the  tertian  organism :  they  have  the  same  hyaline 
appearance,  the  same  indistinct  outline,  and  the  same  sort  of 
ameboid  movement.  While  the  quartan  hyaline  body  is  usually 
described  as  being  of  smaller  size  and  less  ameboid  than  the 

1  Jour.  Exper.  Med.,  i8qS,  vol.  iii,  p.  117;  also  Johns  Hopkins  Hosp.  Bull., 
t8q7  vol.  viii,  p.  236. 


PLATE  VII. 


m  m  ©  9  q  o 


2  3  4  5 


7  8  9  10  11 


12         i  4  *-V^ 


The  Quartan  Parasite. 


1.  Normal  erythrocyte. 

2.  Intracellular  hyaline  form. 

3.  Young  pigmented  intracellular  form.     Note  the  coarseness,  dark  color,  and  scantiness 

of  the  pigment  granules. 

4.  5,  6,  7.  Later  developmental  stages  of  3.    Note  the  peripheral  distribution  of  the  pigment 

in  all  the  parasites  from  3  to  8.  (Compare  size  and  color  of  the  erythrocytes  in  5,  6, 
and  7  with  7,  8,  and  9,  Plate  VI.) 

8.  Mature  intracellular  form.     Note  that   the  stroma  of  the  erythrocyte  is  no  longer 

demonstrable. 

9,  10,  11,  Segmenting  forms.    In  9  are  shown  the  characteristic  radiating  lines  of  pigment. 

(Compare  with  10,  11,  and  12,  Plate  VI,  and  with  10,  ir,  and  12,  Plate  VIII.) 

12.  Large  swollen  extracellular  form.    (Compare  with  13,  Plate  VI.) 

13.  Flagellate  form.    (Compare  with  14,  Plate  VI.) 

14.  Vacuolation  of  an  extracellular  form. 

(E.  F.  Faber,/^.) 


MALARIAL  FEVER. 


455 


similar  tertian  form,  these  differences  are  not  well  enough  marked 
to  .be  Of  practical  application.  At  this  stage  of  its  life  history 
the  organism  of  quartan  fever  possesses  no  distinctive  characteris- 
tics by  which  it  may  be  differentiated  from  the  tertian  variety  of 
a  similar  period  of  growth.  It  is  not  until  it  has  matured  to 
the  stage  of  pigmentation  that  it  is  possible  to  discern  points 
of  distinction  by  which  its  identity  may  be  fixed — characteristics 
which  become  more  and  more  striking  as  development  of  the 
parasite  progresses,  and  which  relate  to  its  color,  outline,  pigment, 
and  ameboid  powers,  as  well  as  to  changes  affecting  its  corpus- 
cular host. 

The  outline  of  the  intracellular  pigmented  form  is  much  more 
distinct  than  that  of  the  tertian,  its  margins  contrasting  rather 
than  blending  with  the  color  of  the  surrounding  erythrocyte. 
The  appearance  of  its  protoplasm  is  also  quite  different,  being  ap- 
parently denser  in  consistence,  more  highly  refractive,  and  unob- 
scured  by  the  color  of  the  overlying  corpuscular  substance. 
Thayer1  has  happily  compared  this  difference  in  refraction  and 
distinctness  of  outline  between  the  tertian  and  quartan  parasites 
to  the  difference  between  a  pale  hyaline  and  a  waxy  cast  in  the 
urine — a  comparison  which  precisely  expresses  these  points  of 
dissimilarity. 

The  pigment  granules,  fine,  yellowish-brown,  and  violently 
motile  in  the  tertian  variety,  are  coarse,  dark  brown  or  almost 
black,  and  sluggishly  motile  in  the  quartan  form.  They  early 
tend  to  form  little  spicula  and  rods,  intensely  dark  in  color,  and 
compactly  arranged,  being  frequently  grouped  together  in  masses 
like  coffee-grounds  in  one  corner  of  the  parasite. 

By  the  time  the  organism  reaches  about  one-half  or  two-thirds 
the  size  of  the  corpuscle  in  which  it  is  contained,  it  may  be  ob- 
served that  its  ameboid  movements,  which  in  the  earlier  stages  of 
its  existence  were  quite  active,  have  now  become  sluggish,  slow, 
and  inconspicuous.  In  consequence  of  this  limited  motility  the 
long  tentacular  shoots  of  protoplasm,  so  familiar  in  the  tertian 
form,  are  not  seen,  the  quartan  parasite  inclining  to  form  resting 
figures,  oval,  round,  or  somewhat  elongated  in  outline.  The 
pigment  does  not  oscillate  violently,  but  moves  about  a  more 
limited  area  with  a  sort  of  deliberate,  tugging  motion.  It  is  dis- 
tributed about  the  periphery,  which  it  parallels  for  only  a  short 
distance,  not  tending  to  produce  the  wreathed  designs  commonly 
observed  in  the  tertian  organism  at  a  corresponding  stage  of  its 
maturity. 

As  the  parasite  matures  its  ameboid  powers  progressively  di- 

1  "Lectures  on  the  Malarial  Fevers,"  New  York,  1897. 


456 


GENERAL  HEMATOLOGY. 


minish,  until  at  a  period  usually  after  the  forty-eighth  hour  fol- 
lowing the  last  paroxysm  little  or  no  motility  either  of  protoplasm 
or  of  pigment  is  distinguishable. 

The  corpuscular  host  meanwhile  undergoes  striking  changes 
in  comparison  to  the  erythrocyte  invaded  by  the  tertian  organism. 
Instead  of  becoming  swollen  and  pale,  as  in  the  latter  instance, 
it  becomes,  on  the  contrary,  shrunken,  darker  colored,  and  some- 
times "brassy."  It  is  not  until  segmentation  is  imminent,  or  from 
about  ten  to  twelve  hours  before  the  impending  paroxysm,  that 
decolorization  of  the  blood  corpuscle  becomes  marked.  At  this 
period  of  its  cycle  the  parasite  measures  about  7  or  8  p.  in  diameter, 
and  is  apparently,  although  not  actually,  unconfined  by  a  cor- 
puscular envelop,  the  latter  now  having  become  rapidly  decolor- 
ized and  finally  quite  invisible. 

As  segmentation  approaches  the  pigment  collects  in  the  center 
of  the  sporocyte,  which  now  becomes  more  opaque  and  develops 
a  number  of  refractive  dots,  which  later  become  the  nuclei  of 
from  six  to  twelve  segments,  developed  by  a  progressive  deepening 
of  parallel  radial  striations  extending  from  the  periphery  to  the 
center  of  the  parasite.  The  segmenting  quartan  parasite  forms 
a  perfect  rosette,  the  individual  spores  being  of  equal  size  and  of 
the  same  shape,  and  the  collected  mass  of  spores  being  very 
symmetrically  arranged.  Coincidentally  with  segmentation  a  new 
group  of  young  hyaline  parasites  may  be  found  in  the  hitherto 
uninvaded  erythrocytes,  indicating  the  beginning  of  another  cycle 
of  the  parasite's  development,  which,  if  unchecked,  persists  for 
seventy- two  hours. 

Thayer1  mentions  a  star-like  arrangement  of  the  pigment  in 
the  early  stages  of  the  segmenting  quartan  organism,  as  if  the 
granules  had  flowed  inward  in  distinct  streams  during  the  process 
of  collection,  and  this  picture  he  is  inclined  to  consider  character- 
istic. The  author  is  able  to  verify  Thayer's  observation,  having, 
in  a  limited  experience  with  the  quartan  parasite,  never  failed  to 
find  this  peculiarity,  its  absence  having  been  equally  conspicuous 
in  malarial  organisms  of  other  types. 

The  quartan  parasite  completes  every  phase  of  its  development 
in  the  circulating  blood,  so  that  all  stages  of  its  cycle,  from  the 
earliest  hyaline  forms  to  the  segmenting  and  flagellate  bodies,  may 
be  studied  in  the  peripheral  blood. 

Extracellular  pigmented  forms,  which  have  parted  with  all 
traces  of  their  corpuscular  capsule  without  having  undergone 
segmentation,  may  also  be  observed.  These  gametes  average  less 
in  diameter  than  similar  forms  of  the  tertian  parasite,  the  largest 

1  Loc.  cit. 


MALARIAL  FEVER. 


457 


of  the  quartan  forms  being  about  equal  in  size  to  the  smallest 
of  the  tertian.  Their  pigment  granules  are  coarse,  very  dark 
colored,  and  situated  chiefly  toward  the  periphery,  with  a  greater 
or  less  drifting  inward  of  individual  pigment  clumps  apparently 
composed  of  two  or  three  agglutinated  coarse  granules.  The 
difference  in  the  distribution  of  the  pigment  in  the  male  and  female 
quartan  gametes  is  more  difficult  to  appreciate  than  in  correspond- 
ing tertian  bodies. 

Flagellate  bodies,  smaller  in  size  and  containing  coarser  gran- 
ules than  corresponding  tertian  forms,  develop  from  these  swollen 
extracellular  parasites,  the  onset  of  flagellation  being  portended 
by  increased  activity  and  centralization  of  the  pigment  in  direct 
anticipation  of  the  appearance  of  the  flagellate  appendages. 

Degenerate  forms  of  the  parasite,  vacuolized,  fragmented,  and 
otherwise  deformed,  may  also  be  observed,  but  with  less  frequency 
than  in  tertian  fever,  probably  for  the  reason  that  extracellular 
forms  of  the  quartan  parasite  are  not  so  numerous  as  those  of  the 
tertian  organism.  The  writer  has  especially  noticed  the  infre- 
quency  of  fragmentation  and  other  deformity  of  those  organisms 
which  have  prematurely  emerged  from  their  corpuscular  host, 
atypical  varieties  of  the  more  mature  free  bodies  being  compara- 
tively much  commonerj 

3.  The  Parasite  of  Estivo- autumnal  Fever  (Plate  VIII). — The 
developmental  cycle  of  the  estivo-autumnal  parasite  exhibits 
marked  irregularity  as  to  the  length  of  time  required  for  its  com- 
pletion, in  contrast  to  the  routine  forty- eight-  and  seventy- two- 
hour  cycles  in  which  the  tertian  and  quartan  organisms  round  out 
their  life  histories.  In  some  instances  the  cycle  of  the  estivo- 
autumnal  parasite  is  of  only  twenty-four  hours'  duration,  while  in 
others  it  is  quite  forty-eight  hours,  or  perhaps  longer.  This  in- 
constancy of  type  is  thought  to  depend  upon  some  peculiarity  of 
the  organism,  by  virtue  of  which  the  time  required  for  its  matu- 
ration may  widely  fluctuate  under  different  conditions  of  quite 
obscure  character.  It  is  not  generally  believed  that  the  common 
types  of  fever,  quotidian  and  tertian,  respectively,  depend  upon 
infection  with  two  special  forms  of  the  estivo-autumnal  parasite, 
although  this  view  is  held  by  some  authors,  notably  by  Mannaberg  1 
and  by  Marchiafava  and  Bignami,2  all  of  whom  recognize  both 
a  quotidian  and  a  tertian  variety  of  the  organism;  the  former, 
furthermore,  describes  a  pigmented  and  an  unpigmented  form  of 
the  quotidian  variety. 

Certain  phases  of  the  young  hyaline  forms  of  the  estivo- 

^othnagel's  "Spec.  Path.  u.  Ther.,"  Vienna,  1899,  vol.  ii,  p.  68. 
2  New  Sydenham  Soc.  Transl.,  London,  1894,  vol.  cl,  p.  1. 


('.  KNKKAL  HEMATOLOGY. 


autumnal  parasite  bear  a  striking  resemblance  to  similar  forms  of 
the  tertian  and  quartan  organisms,  but  other  phases  are,  on  the 
contrary,  just  as  strikingly  dissimilar.  As  a  rule,  the.  cstivo- 
autumnal  amebula  is  much  smaller  than  those  just  described, 
its  margins  are  more  sharply  defined  from  the  corpuscular  sub- 
stance, and  it  appears  to  possess  a  greater  degree  of  refraction. 
But  these  are  minor  points  of  difference,  the  chief  distinction 
relating  to  the  peculiar  morphological  changes  to  be  observed  in 
these  immature  parasites.  At  one  moment  they  may  appear  as 
pale,  rounded  or  somewhat  oval  bodies,  situated  rather  toward 
the  periphery  of  the  corpuscle  than  in  its  center,  and  usually 
possessing  active  ameboid  movements  which  produce  various 
stellate  and  forked  designs.  On  closer  observation  certain  other 
striking  changes  may  be  noted  in  these  round  forms.  These 
changes  consist  in  the  formation  of  the  so-called  ring-shaped 
bodies,  due  to  the  development  of  a  more  or  less  marked  bicon- 
cavity  of  the  hitherto  flattened  hyaline  body,  either  in  its  center, 
in  event  of  which  the  parasite  appears  as  a  true  ring  or  hoop,  or 
more  toward  its  periphery,  in  which  instance  a  figure  resembling 
a  signet-ring  is  produced.  These  figures  remain  visible  for  a 
variable  length  of  time,  the  parasite  meanwhile  being  apparently 
in  a  resting  stage,  but  sooner  or  later  its  ameboid  powers  are 
reasserted,  with  the  result  that  the  biconcavity  abruptly  disappears, 
converting  the  ring-shaped  body  into  its  original  form  of  an 
ameboid,  flattened  disc.  This  successive  alteration  in  shape,  from 
disc  to  ring  to  disc,  regardless  of  the  other  changes  in  shape, 
is  highly  characteristic  of  the  estivo-autumnal  organism,  and  is 
fully  as  valuable  a  diagnostic  sign  as  the  more  striking  pictures  of 
the  maturer  forms,  to  be  considered  later.  The  size  of  the  ring- 
shaped  parasites  varies  from  less  than  2  fi  in  diameter  to  about 
3  ft.  They  are  rarely  situated  in  the  exact  center  of  the  corpuscles, 
more  commonly  being  found  lying  midway  between  the  center 
and  the  periphery,  or,  indeed,  quite  upon  the  latter. 

As  the  parasite  matures,  pigment,  in  the  form  of  a  few  ex- 
ceedingly fine,  scattered  granules,  begins  to  appear.  The  gran- 
ules are  very  few  in  number,  dark  brown  in  color,  and  are  usually 
situated  toward  the  edge  of  the  organism.  They  may  or  may  not 
be  motile,  usually  not.  Strikingly  pigmented  forms  of  the  estivo- 
autumnal  parasite  are  never  observed,  in  marked  contrast  to  the 
abundant  fine  pigment  of  the  tertian  forms  and  to  the  coarse  gran- 
ules typical  of  the  quartan  varieties. 

The  development  of  the  parasite  up  to  this  stage  can  be  studied 
in  the  peripheral  blood,  but  the  older  forms  of  the  pigmented 
bodies,  and  their  final  division  into  spores,  by  segmentation,  occur 


ugiuirtf 

0f  THE  _ 


PLATE  VIII. 


2  3 


5  6 


10  11 


12  13  14 


15 


17 


22 


23 


24  m 


U 

26 


25 


The  Estivo-Autumnal  Parasite. 


1.  Normal  erythrocyte. 

2,  3.    Young  hyaline  ring-forms.  . 
4,  5,  6.  Intracellular  hyaline  forms.    In  4  the  parasite  appears  as  an  irregularly  shaped  disc 

with  a  thinned-out  central  area.    In  s  and  6  its  ameboid  properties  are  obvious. 

7.  Young  pigmented  intracellular  form.    Note  the  extreme  delicacy  and  small  number  of 

the  pigment  granules.    (Compare  with  6,  Plate  VI,  and  with  3,  Plate  VII.) 

8,  9.  Later  developmental  stages  of  7. 
10,  11,  12.  Segmenting  forms. 

13  14.  Crescentic  forms  at  early  stages  of  their  development. 

15,  16,  17,  18,  19.  Crescentic  forms.  In  15  and  19  a  distinct  "bib"  of  the  erythrocyte  is  visible. 

Vacuolation  of  a  crescent  is  shown  in  18,  and  polar  arrangement  of  the  pigment  in  17. 

20.  Oval  form. 

21,  22-  Spherical  forms. 

23.  Flagellate  form. 

24.  Vacuolation  and  deformity  of  a  spherical  form. 

25.  Vacuolated  leucocyte  apparently  enclosing  a  dwarfed  and  shrunken  crescent. 

26.  Remains  of  a  shrunken  spherical  form. 


(E.  F.  Faber, /,?<:.) 


MALARIAL  J'KVKK. 


459 


almost  exclusively  in  the  deeper  circulation,  and  must  be  followed 
out  in  blood  obtained  from  one  of  the  internal  organs,  such  as 
the  spleen,  which  may  be  aspirated  for  this  purpose,  although 
the  procedure  is  not  without  risk  to  the  patient.  In  the  finger 
blood  the  writer  has  never  seen  presegmenting  forms  more  mature 
than  those  represented  by  the  young,  slightly  pigmented  parasite, 
and  has  never  had  the  good  fortune  to  meet  with  segmenting 
bodies  except  in  specimens  derived  from  the  spleen.  The  general 
rule  is  to  find  in  the  peripheral  blood  nothing  more  than  hyaline, 
ameboid,  and  ring-shaped  bodies,  or,  perhaps,  a  few  organisms 
containing  two  or  three  minute  granules  of  pigment. 

If,  now,  a  drop  of  blood,  aspirated  from  the  spleen,  is  examined, 
the  remainder  of  the  parasite's  cycle  may  be  traced  with  fair 
accuracy.  As  it  approaches  the  stage  of  segmentation,  the  parasite 
develops  into  a  spherical  body,  measuring  from  about  2  to  6  ft 
in  diameter,  and  having  a  distinct  outline  which  limits  it 
from  the  surrounding  substance  of  the  erythrocyte,  which  it 
only  partly  fills.  The  pigment  granules,  which  by  this  time  are 
moderately  but  never  strikingly  increased  in  number,  show  a 
marked  tendency  to  become  concentrated  near  the  center  of  the 
organism.  They  here  exist  as  a  tightly  clumped,  compact  mass, 
in  which  the  identity  of  the  individual  granules  is  completely  lost, 
as  they  have  now  become  fused  into  a  single  distinct,  dark-colored, 
round  or  somewhat  elongated  mass. 

As  segmentation  commences  the  parasite  becomes  opaque, 
minute  refractive  areas  paralleling  the  periphery  develop,  and 
radial  shadings,  which  later  divide  the  body  usually  into  from 
eighteen  to  twenty  spores,  become  apparent.  The  segmenting 
body  is  smaller  than  that  of  the  tertian  and  quartan  parasites,  but 
it  usually  resembles  the  former  as  to  the  arrangement  and  number 
of  the  individual  segments. 

A  marked  characteristic  of  the  estivo-autumnal  infections  is 
the  early  occurrence  of  degenerative  changes  in  the  invaded 
erythrocytes.  These  changes,  the  "  erythropyknosis  "  of  the  Italian 
school,  consist  in  the  development  of  a  pronounced  "brassy" 
appearance  of  the-  blood  cell,  together,  in  many  instances,  with 
distinct  crenation  along  its  periphery  and  in  various  portions  of 
its  flat  surface.  Occasionally  there  appears  to  be  a  distinct  con- 
centration of  the  hemoglobin  about  the  parasite,  leaving  portions 
of  the  corpuscle  quite  colorless.  This  corpuscular  degeneration 
occurs  early,  even  in  those  cells  occupied  by  the  youngest  hyaline 
bodies,  and  grows  more  and  more  marked,  as  a  rule,  as  the  parasite 
matures.  Simple  decolorization  of  the  erythrocyte  appears  to 
follow  no  fixed  rule,  for  segmenting  bodies  have  been  observed 


460 


GENERAL  HEMATOLOGY. 


both  in  perfectly  hyaline  and  in  apparently  unchanged  corpuscles. 
In  Thayer's  experience  the  rim  of  the  blood  cell  surrounding  the 
parasite  has  usually  been  entirely  devoid  of  color. 

After  the  infection  has  existed  for  a  week  or  more  examination 
of  the  peripheral  blood,  which  until  now  has  contained  perhaps 
only  ring-shaped  organisms,  reveals  the  presence  of  other  highly 
characteristic  forms  of  the  estivo-autumnal  parasite,  the  round, 
ovoid,  and  crescentic  bodies,  all  belonging  to  the  crescent  group, 
representing  the  gamete  forms  of  the  organism.  These  forms, 
which  are  never  present  in  the  circulation  during  the  first  days 
of  the  fever,  are  prone  to  persist  in  the  blood  for  a  long  period 
after  the  disappearance  of  the  earlier  forms  of  the  parasite,  and- 
even  after  all  the  clinical  manifestations  of  the  attack  have  van- 
ished. Unlike  other  forms  of  the  malarial  parasite,  those  of  the 
crescent  group  are  peculiarly  resistant  to  the  effects  of  the  ad- 
ministration of  quinin,  large  doses  of  this  drug  having  in  many 
instances  no  appreciable  effect  in  causing  their  disappearance 
from  the  peripheral  circulation. 

Crescents  are  of  intracellular  origin,  being  transformed  stages 
of  the  full-grown,  pigmented,  intracellular  spherical  bodies  which 
have  not  been  involved  in  the  process  of  segmentation.  These 
gamete  forms  continue  their  development  within  the  corpuscle, 
from  which  they  derive  more  and  more  pigment,  thus  causing 
progressive  decolorization  of  their  host,  until  finally  all  that  re- 
mains of  the  corpuscle  is  a  thin  shell  surrounding  the  crescent. 
As  its  growth  progresses  the  parasite  first  loses  its  regular  spheri- 
cal contour,  and  then  becomes  drawn  out  into  a  long,  narrow, 
spindle-shaped  body,  which  finally  becomes  bent  in  the  shape 
of  a  crescent,  the  convexity  of  which  lies  next  to,  and  for  some 
distance  parallels,  one  margin  of  the  now  almost  colorless  eryth- 
rocyte. 

Owing  to  the  fact  that  the  early  development  of  the  crescents 
occurs  almost  exclusively  in  the  deeper  circulation,  only  the  later 
phases  of  their  evolution  are  ordinarily  observed  in  the  peripheral 
blood.  In  fresh  blood  they  appear  as  highly  refractive,  crescent- 
shaped  bodies,  measuring  about  6  or  8  jul  from  pole  to  pole,  and 
possessing  a  distinct  double  outline,  as  if  they  consisted  of  a  central 
darker  body  inclosed  in  a  lighter  colored  membranous  envelop. 
Adhering  to  the  concave  surface  of  the  crescent  a  more  or  less 
distinct  "bib,"  the  remnant  of  the  corpuscular  host,  may  usually 
be  observed.  It  varies  in  color  from  pale  yellow  to  an  almost 
indistinguishable  shade  of  light  lemon,  yet  it  always,  on  close 
observation,  retains  sufficient  of  the  corpuscular  color  to  distin- 
guish it  from  the  parasite  to  which  it  is  attached.    The  "bib" 


MALARIAL  FEVER. 


461 


completely  bounds  the  concavity  of  the  crescent  in  some  instances, 
extending  from  pole  to  pole;  in  other  instances — and  this  is  of 
commoner  occurrence— it  is  of  smaller  size,  extending  over  only 
the  central  portion  of  the  concavity.  Occasionally  crescentic 
bodies  totally  devoid  of  all  traces  of  their  corpuscular  host  are 
found,  but  these  forms  are  rare.  The  pigment  is  usually  arranged 
in  a  moderately  compact  clump  or  wreath-like  design,  in  the 
center  of  the  crescent;  less  commonly  the  granules  are  scattered 
along  the  long  axis;  and  very  rarely  a  distinct  polar  grouping  of 
the  pigment  at  both  ends  of  the  crescent  is  seen.  The  pigment 
granules  may  or  may-  not  show  active  motility.  In  the  fresh 
specimen  it  will  be  noted  that  in  the  male  crescents  the  pigment 
tends  to  collect  centrally  in  an  irregular  mass,  while  in  the  female 
crescents  it  is  generally  arranged  in  the  form  of  a  wreath. 

The  ovoid  bodies,  which  are  simply  transitional  forms  of  the 
crescents,  are  of  symmetrically  oval  shape,  and  show  the  same 
refractive  protoplasm  and  apparently  double  outline  observed  in 
the  latter.  The  pigment,  which  is  generally  motionless,  is  ar- 
ranged in  an  elongated  clump  in  the  center  of  the  ovoid,  and  a 
partly  decolorized,  bib-like  corpuscular  attachment  apparently 
clings  to  one  side  of  the  body.  The  long  diameter  of  the  ovoid 
body  measures  approximately  5  or  6  p.  and  its  short  axis  is  about 
2  or  3  (J.  across. 

The  round  forms,  derived  from  the  crescentic  and  ovoid  bodies, 
are  the  direct  antecedents  of  the  flagellate  organisms.  They 
appear  as  perfect  spheres,  4  or  5  fJ.  in  diameter,  either  attached 
to  a  more  or  less  yellowish  remnant  of  the  erythrocyte  or  lying 
entirely  free.  Their  pigment  is  prone  to  form  a  central  wreathed 
or  ringed  design,  or  to  be  massed  centrally. 

The  approach  of  flagellation  is  preceded  by  unusual  activity  of  m 
the  central  pigment  mass,  coincidentally  with  which  indications 
of  motility  about  the  periphery  of  the  parasite  become  apparent. 
The  flagella,  which  are  finally  seen  to  reach  out  from  different 
points  on  the  periphery  of  the  body,  are  similar  in  appearance  to 
those  of  the  tertian  and  quartan  organisms.  Their  size,  however, 
is  about  midway  between  that  of  these  forms.  Rarely,  a  free 
flagellum  may  be  seen  to  penetrate  and  fertilize  a  female  gamete 
(represented  by  one  of  the  round  non-flagellate  forms),  which 
in  consequence  becomes  actively  motile,  loses  its  spherical  con- 
tour, and  exhibits  violent  agitation  of  its  contained  pigment.  ^ 

Degenerative  changes  of  the  crescentic,  ovoid,  and  round  bodies 
occur,  being  evidenced  by  the  development  of  vacuoles  and  occa- 
sionally by  apparent  fragmentation. 


462 


GENERAL  HEMATOLOGY. 


Pigmented  leucocytes  are  found  in  the  blood 
Pigmented  Leu-  of  all  types  of  malarial  infection,  and  this  fact 

cocytes  and     alone,  irrespective  of  the  presence  of  the  parasites 
Phagocytosis,  themselves,  is  an  extremely  valuable  diagnostic 
clue  to  the  condition. 

In  tertian  and  quartan  infections  the  large  mononuclears  and 
polynuclear  neutrophiles  are  the  pigment-bearing  cells,  the  gran- 
ules being  found  scattered  either  in  fine  masses  or  in  fused  angular 
blocks  throughout  the  bodies  of  the  leucocytes.  Although  both  of 
these  forms  of  leucocytes  show  this  evidence  of  having  acted  the 
role  of  phagocytes,  actual  visual  proof  of  the  performance  of  this 
function  by  the  mononuclear  forms  is  wanting.  The  phenomenon 
of  the  phagocytosis  by  the  polynuclear  leucocytes  may,  however, 
be  watched  in  the  fresh  specimen,  and  these  cells  may  be  seen 
to  engulf  bits  of  free  pigment,  flagellate  bodies,  bastard  forms  of 
extracellular  parasites,  and  even,  rarely,  true  segmenting  bodies. 
Distinct  periodicity  characterizes  the  performance  of  phagocytosis 
in  tertian  and  quartan  infections,  this  process  being  most  con- 
spicuous at  the  time  of  segmentation,  during  and  shortly  after 
the  paroxysm,  when  the  extracellular  forms  of  the  organism  are 
present  in  the  blood  in  greatest  number.  Phagocytosis  is  some- 
times seen  during  the  interparoxysmal  interval,  when  only  the 
extracellular  forms  of  parasites  which  have  prematurely  escaped 
from  their  corpuscular  host  are  attacked. 

In  estivo- autumnal  infections  macrophages,  derived  from  the 
spleen,  bone  marrow,  liver,  and  blood  vessel  endothelium,  act  as 
phagocytes,  as  well  as  the  mononuclear  and  polynuclear  cells, 
which  alone  exercise  this  function  in  the  regularly  intermittent 
fevers.  Phagocytosis  is  much  less  periodical  than  in  tertian  and 
quartan  infections,  for  while  it  is  true  that  pigmented  leucocytes 
are  most  numerous  in  the  blood  at  the  time  of  segmentation,  it  is 
also  true  that  they  may  be  observed  in  great  numbers  during 
the  interval — a  fact  which  is  explained  chiefly  by  the  practically 
continuous  segmentation  which  goes  on  in  these  infections  because 
of  the  presence  in  the  blood  of  multiple  groups  of  the  parasite. 
Phagocytosis  in  estivo-autumnal  fever  differs  from  that  of  tertian 
and  quartan  infections  in  that  in  the  former  inclusion  of  both 
parasite  and  corpuscular  host  may  occasionally  be  observed — a 
phenomenon  which  does  not  occur  in  the  latter.  Thus,  in  addi- 
tion to  free  pigment  and  extracellular,  segmenting,  and  flagellate 
forms,  the  phagocytic  leucocytes  are  found  also  to  contain  whole 
or  portions  of  necrobiotic  erythrocytes,  some  of  the  latter,  perhaps, 
inclosing  parasites.    Osier 1  has  observed  the  phagocytosis  of 

1  Brit.  Med.  Jour.,  1887,  vol.  i,  p.  556. 


MALARIAL  LEVER. 


crescentic  forms,  and  the  writer  believes  that  he  has  seen  the 
result  of  this  phenomenon  in  a  single  instance.  (See  Plate  VIII, 
Fig.  25.) 


DIFFERENTIAL  TABLE  OF  THE  MALARIAL  PARASITES. 


Tertian  Parasite. 


Cycle,  Forty-eight  Hours. 


Hyaline  body  larger  than 
that  of  quartan  and  esti- 
vo-autumnal  organisms; 
outline  indistinct;  ame- 
boid movements  exceed- 
ingly active;  long  pseu- 
dopodia  common. 


Pigment  granules  fine, 
very  active,  and  of  yel- 
lowish brown  color; 
more  or  less  peripher- 


ally arranged. 


Mature  parasite  about  7  \i 
in  diameter. 

Segmenting  body  consists 
of  from  15  to  30  seg- 
ments, arranged  in  an 
irregular  racemose  fig- 
ure about  one  or  more 
•central  pigment  clumps. 


Preflagellate  form  consists 
of  swollen,  spherical 
pigmented  body  as  large 
as  10  to  12  /j  in  diame- 
ter. 


Flagellate  form  larger  than 
that  of  quartan  and 
estivo-autumnal  para- 
site. 

Erythrocyte  becomes  very 
pale  and  swollen. 


Quartan  Parasite. 


Cycle,  Seventy-two  Hours. 


Hyaline  body  smaller  than 
that  of  tertian,  but  usu- 
ally larger  than  that  of 
estivo-autumnal  organ- 
ism; outline  distinct; 
ameboid  movements 
slow,  except  in  early 
forms;  marked  pseudo- 
podial  branching  un- 
common. 

Pigment  granules  coarse, 
sluggish,  and  of  dark- 
brown  color;  peripheral 
arrangement  striking. 


Mature  parasite  about  5  \i 
in  diameter. 

Segmenting  body  consists 
of  from  6  to  12  seg- 
ments, arranged  in  regu- 
lar rosette  form  about  a 
single,  compact,  central 
pigment  mass,  the  latter 
often  being  radially 
grouped  in  the  early 
stages  of  sporulation. 


Preflagellate  form  consists 
of  swollen,  spherical 
pigmented  body  as  large 
as  6  to  8  u  in  diameter. 


Flagellate  form  smaller 
than  that  of  tertian  and 
estivo  -  autumnal  para- 
site. 

Erythrocyte  becomes  dark 
and  contracted. 


Estivo-autumnal  Parasite. 


Cycle,  Twenty-four  to  Forty- 
eight  Hours  or  Longer. 


Hyaline  body  smaller 
than  that  of  tertian  and 
quartan  organisms;  out- 
line very  sharp  and  dis- 
tinct; ameboid  move- 
ments active  in  early 
stages;  ring-  and  disc- 
shaped forms. 


Pigment  granules  ex- 
ceedingly fine  and 
scanty;  may  be  either 
motionless  or  motile; 
peripheral  arrangement 
often  marked. 

Mature  parasite  from 
1.5  to  7  fi  in  diameter. 

Segmenting  body  consists 
of  from  18  to  20  or 
more  segments,  ar- 
ranged either  as  a 
regular  rosette  or  irreg- 
ularly about  a  single 
compactly  fused  cen- 
tral pigment  clump. 


Preflagellate  form  con- 
sists of  spherical  pig- 
mented body,  5  to  6  u 
in  diameter,  and  de- 
rived from  crescentic- 
and  ovoid  forms,  with 
which  they  are  asso- 
ciated. 

Flagellate  form  smaller 
than  that  of  tertian, 
but  larger  than  that  of 
quartan,  parasite. 

Erythrocyte  becomes 
brassy  and  crenated. 


464 


GENERAL  HEMATOLOGY. 


Technic  of  the  Blood  Examination. — For  diagnostic  purposes 
the  fresh,  unstained  blood  film  should  be  invariably  preferred  to 
the  dried,  stained  specimen,  for  in  the  latter  not  only  are  the  ame- 
boid movements  of  the  parasite  and  the  dancing  of  the  pigment 
necessarily  lost,  but  much  of  the  morphology  and  the  finer  struc- 
ture of  the  organism  is  also  greatly  altered.  The  blood  is  obtained 
in  the  usual  manner,  and  a  drop  used  which  is  small  enough  to 
insure  an  exceedingly  thin  film,  consisting  of  a  single  layer  of 
corpuscles,  each  lying  edge  to  edge,  so  that  every  portion  of  their 
flat  surfaces  may  be  readily  searched  for  foreign  bodies.  Thick, 
dehemoglobinized  films  are  useful  for  the  diagnostic  examination 
of  blood  in  which  the  parasites  are  very  scanty,  but  they  are 
unsuitable  for  accurate  histological  study.  (See  p.  77.)  If  the 
examination  is  likely  to  be  prolonged,  it  is  advisable  to  ring  the 
cover-glass  with  cedar  oil  or  with  vaselin,  to  prevent  crenation  of 
the  corpuscles. 

Dried  blood  films,  prepared  in  the  usual  way,  may  be  used  in 
case  the  specimens  must  be  sent  some  distance  for  examination. 
Such  specimens  must  be  stained  with  various  anilin  dyes,  as  already 
directed.  Polychrome  methylene-blue,  in  the  form  of  Wright's 
or  Goldhorn's  solutions,  gives  the  sharpest  differentiation  of  the 
parasite's  histological  structure,  but  solutions  of  thionin  and  of 
eosin  and  methylene-blue  also  will  prove  useful.  (See  pp.  82 
and  88.) 

No  magnification  can  be  too  great  in  studying  the  finer  points 
of  the  malarial  parasite,  so  that  a  TVinch  oil-immersion  objective, 
with  at  least  a  ij-inch  ocular,  should  be  habitually  employed  for 
the  microscopical  examination.  While  it  is  frequently  convenient 
to  search  for  individual  parasites  with  a  f  or  a  J-inch  lens,  one 
cannot  well  dispense  with  an  immersion  objective  in  distinguishing 
their  finer  characteristics.  The  substage  condenser  and  iris 
diaphragm  should  be  so  adjusted  that  the  field  is  dimly  illuminated, 
and  not  drowned  in  a  flood  of  white  light.  When  the  ameboid 
movements  of  the  parasite  are  to  be  studied  at  length,  a  warm 
stage  is  useful,  but  not  essential,  if  the  temperature  of  the  room 
is  not  too  low. 

The  best  time  for  the  examination  is  a  few  hours  before  the 
onset  of  the  expected  paroxysm,  at  which  period  it  is  common  to 
find  full-grown  pigmented  organisms  and  often  an  occasional 
segmenting  form,  if  the  specimen  is  from  a  tertian  or  quartan 
infection.  In  estivo- autumnal  fever  relatively  large  ring-  and 
disc-shaped  bodies,  containing  exceedingly  delicate  pigment  gran- 
ules, are  usually  abundant  at  this  time.  Intracellular  hyaline 
forms  are  most  numerous  in  the  blood  a  few  hours  subsequent  to 
the  paroxysm  in  all  three  forms  of  the  infection. 


MALARIAL  FKVKR. 


465 


The  writer  would  urge  the  beginner  systematically  to  study  the 
development  of  a  group  of  parasites  by  examining  the  blood  of  a 
single  case  of  malarial  fever  at  frequent  intervals  between  the 
paroxysms.  For  example,  the  life  history  of  the  tertian  parasite, 
from  the  youngest  hyaline  amebula  to  the  segmenter  and  the 
flagellate  body,  may  be  traced  in  most  cases  of  tertian  fever  if 
the  blood  is  examined  every  three  or  four  hours,  day  and  night, 
for  a  period  of  forty- eight  hours.  Such  a  collated  series  of  ob- 
servations, although  they  entail  close  and  tiresome  application  for 
the  time,  will  prove  more  profitable  to  the  student  in  his  compre- 
hension of  the  organism's  developmental  cycle  than  dozens  of 
haphazard  examinations  made  in  many  different  cases  at  odd 
times. 

To  the  unpractised  eye  a  number  of  artefacts  occurring  in 
fresh  blood  specimens  may  for  a  time  be  confused  with  the  malarial 
parasite,  but  careful  observation  linked  to  an  increased  familiarity 
with  the  appearance  of  the  organism  and  of  its  counterfeits  will 
eliminate  such  sources  of  error.  The  following  are  the  principal 
objects  which  require  to  be  differentiated  from  the  malarial  par- 
asite: (1)  The  central  biconcavity  of  the  normal  erythrocytes; 
(2)  morphological  changes  in  the  erythrocytes,  and  (3)  hemokonias. 

1.  At  first  glance  the  pale  central  biconcavity  of  the  erythro- 
cyte somewhat  resembles  the  young  hyaline  tertian  parasite,  for 
each  has  an  indistinct  outline  which  merges  with  the  surrounding 
corpuscular  substance.  But  the  parasite  is  rarely  in  the  center  of 
the  blood  cell,  it  is  actively  ameboid,  and  it  possesses  a  character- 
istic pearly-gray  appearance.  On  the  other  hand,  the  pale  area 
of  the  corpuscle  is  in  the  center  of  the  normally  shaped  blood  cell, 
it  never  exhibits  ameboid  powers,  and  its  appearance  is  clean 
white  or  yellowish- white.  It  is,  of  course,  uncolored  in  the  stained 
specimen. 

2.  The  morphological  changes  in  the  erythrocyte,  which  may 
be  mistaken  for  malarial  organisms,  are  those  produced  by  vac- 
uolization, crenation,  and  fragmentation  of  these  cells.  Vacuoles 
appear  as  highly  refractive,  clean-cut,  spherical  bodies  which 
possess  more  or  less  oscillating,  rotary  motility,  in  contrast  to  the 
dimmer,  more  vaguely  outlined,  truly  ameboid  forms  of  the  hya- 
line malarial  parasite.  The  spicula  of  crenated  red  cells  may 
in  a  very  dim  illumination  of  the  object  appear  at  first  glance 
somewhat  like  the  coarse  granules  of  the  mature  pigmented  par- 
asite, but  a  change  of  focus  and  a  wider-open  diaphragm  imme- 
diately dispels  the  illusion.  Fragmentation  of  the  erythrocytes, 
as  the  result  of  thermic  influences,  may  produce  a  most  bizarre 
and  peculiar  variety  of  designs,  the  most  confusing  of  which  is  a 

3° 


466 


GENERAL  HEMATOLOGY. 


sort  of  flagellate  appendage  which  appears  to  originate  in  a  frag- 
mented sphere  of  corpuscular  substance,  to  which  it  is  attached. 
The  size  of  this  body,  however,  is  far  too  small  to  be  mistaken 
seriously  for  a  true  malarial  flagellate  body,  for  its  spherical 
portion,  which  is  unpigmented  and  tinged  with  hemoglobin, 
measures  only  about  2  fi  in  diameter;  while  the  flagellate  ap- 
pendage, usually  single,  is  represented  by  a  colorless,  thin  line 
not  often  longer  than  3  or  4  p,  and  tremulously  motile,  not  ame- 
boid like  the  flagellum  of  the  malarial  body.  This  sort  of  a 
flagellate  figure  is  very  commonly  seen  in  blood  slides  which  have 
become  chilled. 

3.  Hemokonia  are  readily  distinguished  by  their  very  small 
size,  spherical  contour,  and  glistening,  fat-like  appearance.  It 
sometimes  happens  that  one  of  these  granules  of  "blood  dust,'' 
in  its  Brownian  excursion  across  the  field  of  the  microscope,  lies 
over  the  flat  surface  of  an  erythrocyte,  simulating  for  the  moment 
a  small,  hyaline,  intracellular  parasite.    It  seems  probable,  also, 
that  one  of  these  granules,  observed  just  at  the  instant  it  crosses 
the  rim  of  the  blood  cell,  has  been  mistaken  for  a  hyaline  spore 
in  the  act  of  invading  an  erythrocyte,  by  those  who  believe  that 
they  have  witnessed  this  remarkable  phenomenon.    (See  p.  452-) 
Well-marked  anemia,  developing  early  during 
Hemoglobin  the  course  of  the  disease,  and  proportionate  in 
and         degree  to  the  severity  of  the  attack,  is  a  con- 
Erythrocytes.  spicuous  clinical  sign  in  the  malarial  fevers. 

Dionisi,1  Thayer,2  and  other  authors  have  ob- 
served that  a  loss  of  hemoglobin  and  a  diminution  in  the  number 
of.  erythrocytes  occur  after  every  paroxysm,  this  being  due  largely 
to  the  destruction  of  immense  numbers  of  parasite-containing  cor- 
puscles by  the  maturation  of  the  organisms,  and  in  part  to  the 
presence  in  the  blood  of  other  substances  destructive  to  the  un- 
invaded  red  cells.  The  loss  is  especially  marked  after  the  early 
paroxysms,  being  of  slighter  degree  after  those  occurring  later  in 
the  course  of  the  disease.  On  the  other  hand,  during  the  paroxysm 
a  tendency  on  the  part  of  the  erythrocytes  to  increase  in  number 
has  been  noted. 

The  loss  is  more  moderate  in  the  regularly  intermittent  tertian 
and  quartan  types  of  malaria  than  in  the  estivo-autumnal  form. 
In  the  former  types,  the  regenerative  powers  of  the  blood  are 
usually  prompt  and  vigorous,  so  that  the  normal  number  of  cells 
is  almost  restored  by  the  onset  of  the  succeeding  paroxysm.  It 
is  owing  to  this  fact  that  repeated  paroxysms  must  occur  before 
the  anemia  becomes  striking. 

1  Lo  Sperimentale,  1891,  f.  iii  and  iv3  p.  284.  .  2  Loc.  ctt. 


MALARIAL  FEVER. 


467 


In  the  estivo-autumnal  form  the  loss  is  far  greater,  a  decrease 
of  500,000  or  more  corpuscles  per  c.mm.  sometimes  occurring 
after  a  single  paroxysm,  so  marked  a  loss  as  this  being  associated 
especially  with  cases  in  which  excessive  numbers  of  parasites  are 
present  in  the  blood.  Even  in  non-febrile  cases  of  larval  malarial 
fever  Marchiafava  and  Bignami 1  have  observed  more  or  less 
anemia.  Organisms  of  the  crescent  group  appear  to  exert  no 
influence  in  causing  diminution  in  the  number  of  erythrocytes. 
Regeneration  of  the  blood  is  slow  in  the  estivo-autumnal  fever, 
so  that  the  loss  of  hemoglobin  and  of  corpuscles  is  not  made  up 
during  an  interparoxysmal  interval,  in  consequence  of  which  more 
marked  and  graver  anemias  are  commoner  than  in  the  tertian 
and  quartan  fevers.  If  the  anemia  is  markedly  developed  during 
the  early  stages  of  the  infection,  the  corpuscular  decrease  is  ag- 
gravated slightly,  if  at  all,  by  the  following  paroxysms. 

In  malarial  hemoglobinuria  an  enormous  destruction  of  cor- 
puscles occurs,  "a  destruction,"  in  the  words  of  Thayer,2  "too 
great^  probably,  to  be  dependent  wholly  on  the  disintegration  of 
parasitiferous  elements.  We  are  compelled  ...  to  suppose 
the  existence  of  some  condition  which  renders  the  uninfected  red 
blood  corpuscles  unusually  vulnerable,  possibly  some  change  in 
the  blood  serum  by  which  its  isotonicity  is  markedly  disturbed." 

Usually  the  hemoglobin  loss  is  relatively  ,  less  than  the  cor- 
puscular decrease,  fairly  high  color  indices  being  the  general  rule, 
but  in  some  cases  both  are  parallel.  In  estimates  made  by  the 
author  m  45  cases  of  malarial  fever,  nearly  all  of  the  tertian  type, 
the  hemoglobin  averaged  67  per  cent,  of  normal,  ranging,  in  the 
individual  case,  from  19  to  97  per  cent. 

The  variations  in  hemoglobin  were  as  follows :  • 

Hemoglobin  Percentage. 

From  90-100  

80-90   

70-80   

60-70  

50-60   

40-50   

30-40   

a 

20-30   

a 

IO-20   

Average,     67  per  cent. 
Maximum,  97  " 
Minimum,  19  " 

1  Loc.  cit. 


Number  of  Cases. 

  2 

 12 

 II 

  7 

 4 

  5 

  2 

......  1 

  1 


Loc.  cit. 


468  GENERAL  HEMATOLOGY. 

The  loss  of  corpuscles  varies  within  wide  limits,  being  most 
marked  in  severe  and  in  long-standing  cases.  Counts  as  low  as 
500,000  per  c.mm.  have  been  reported,1  and  the  number  falls  to 
from  1,000,000  to  2,000,000  in  a  considerable  proportion  of  cases. 
In  the  above  series  the  average  of  the  45  counts  showed  2,585,688 
erythrocytes  per  c.mm.,  individual  cases  varying  from  1,410,000  to 
5,250,000.  The  range  of  the  counts  is  shown  thus,  in  tabular 
arrangement : 

Erythrocytes  per  c.mm.  Number  of  Cases. 

Above    5,000,000   2 

From      4,000,000-5 ,000,000  22 

"        3,000,000-4,000,000   8 

"        2,000,000-3,000,000  8 

"  ;      1,000,000-2,000,000   5 

Average,     2,585,688  per  c.mm. 
Maximum,  5,250,000 
Minimum,  1,410,000  " 

In  7  cases  clinically  designated  as  "malarial  cachexia,"  in 
which  parasites  were  not  found  in  the  circulating  blood,  the  fol- 
lowing results  were  obtained:  hemoglobin  ranged  from  40  to  52 
per  cent.,  the  average  being  45.5;  color  index,  from  0.41  to  1.13, 
averaging  0.66;  and  erythrocytes,  from  2,300,000  to  4,861,000 
per  c.mm.,  with  an  average  of  3,406,250. 

As  regeneration  of  the  blood,  which  is  generally  slow,  takes 
place,  the  normal  percentage  of  hemoglobin  is  reached  more 
slowly  that  that  of  the  corpuscles— in  fact,  in  some  instances  of 
post-malarial  anemia  subnormal  hemoglobin  percentages  persist 
for  indefinite  periods  after  convalescence  has  been  established. 

Histological  changes  in  the  erythrocytes  are  marked  in  relation 
to  the  severity  of  the  anemia.  Pallor  of  the  corpuscles  is  often 
conspicuous,  and  poikilocytosis  and  deformities  of  size  are  present 
in  severe  cases.  In  such  instances  small  percentages  of  normo- 
blasts and  of  atypical  nucleated  forms  are  not  infrequently  found, 
sometimes  in  association  with  an  occasional  megaloblast.  In 
severe  cases  both  polychromatophilia  and  basic  granular  degenera- 
tion of  the  erythrocytes  are  familiar  findings. 

The  peculiar  "brassy"  appearance  of  the  erythrocytes  (  globuli 
rossi  attonati"  of  the  Italians)  invaded  by  the  estivo-autumnal 
parasite  has  already  been  noted  (p.  459)-  .  , 

In  tertian  fever,  and  only  in  this  type  of  malaria,  the  infected 
erythrocytes,  when  stained  by  Romanowsky's  method,  show 
SchiifTner's  granules,  recognized  as  a  reddish  mottling  of  portions 
of  the  cells  not  occupied  by  the  parasites. 

1  Kelsch,  Arch.  Physiol,  1875,  vol.  ii,  p.  690;  ibid.,  1876,  vol.  hi,  p.  49°- 


MALARIAL  FEVER. 


469 

In  estivo-aulumnal  fever  the  infected  cells,  when  similarly 
stained,  show  minute  clefts  and  cracks  and  coarse,  irregular  areas 
reacting  basically.  Stephens  and  Christophers1  demonstrate  these 
signs  of  necrobiosis  by  staining  chloroform-fixed  films  by  the 
Romanowsky  method  for  one  hour,  and  differentiate  them  from, 
the  familiar  basic  stippling  and  the  reddish  Schuffner's  granules 
of  erythrocytes  harboring  the  tertian  parasite. 

The  following  four  types  of  post-malarial  anemia  are  distin- 
guished by  Bignami  and  Dionisi.2 

1.  Anemias  in  which  examination  of  the  blood  shows  altera- 
tions similar  to  those  observed  in  secondary  anemias,  from  which 
they  differ  only  in  that  the  leucocytes  are  diminished  in  number. 
The  greater  part  of  these  cases  go  on  to  recovery;  a  few,  without 
any  further  change  in  the  hematological  condition,  pursue  a  fatal 
course. 

2.  Anemias  in  which  the  examination  of  the  blood  shows  altera- 
tions similar  to  those  seen  in  pernicious  anemia— prevalence  of 
megaloblasts.    These  cases  end  fatally. 

3.  Anemias  which  are  progressive  as  a  result  of  the  lack  of 
compensation  by  the  marrow  for  losses  brought  about  by  the 
infection.  At  autopsy  the  marrow  of  the  long  bones  is  found  to 
be  wholly  yellow,  while  the  marrow  of  the  flat  bones  is  also  poor 
in  nucleated  erythrocytes. 

4.  Chronic  anemias  of  the  cachectic,  which  differ  from  the 
above-mentioned  types  by  clinical  and  anatomical  characteristics 
m  that  the  special  symptoms  of  malarial  cachexia  prevail,  while 
one  observes,  postmortem,  a  sort  of  sclerosis  of  the  bone  marrow. 
The  marrow  of  the  long  bones  is  red  and  of  an  increased  con- 
sistency; the  giant  cells  are  very  numerous  and  many  are  necrotic; 
the  nucleated  erythrocytes  are  very  rare,  and  the  colorless  poly- 
nuclear  corpuscles  are  present  in  small  numbers. 

Distinct  leucopenia,  or  at  least  an  absence 
Leucocytes,  of  leucocytosis,  is  almost  invariably  found  in  the 
uncomplicated  cases  of  malarial  fever,  the  excep- 
tions to  this  general  rule  occurring  during  the  grave  paroxysms 
of  the  pernicious  type  of  fever. 

The  subnormal  range  of  the  leucocytes  in  malarial  fever  was 
early  noted  by  Kelsch,3  and  has  been  repeatedly  confirmed  by 
other  investigators  since  the  former's  statement  of  the  fact.  Bill- 
ings,4 in  particular,  has  carefully  studied  this  question,  and  his 

1  Brit.  Med.  Jour.,  1903,  vol.  i,  p.  730. 

2  Centralbl.  f.  allg.  Path.  u.  path.  Anat.,  1894,  vol.  v,  p.  422.  (Cited  bv  Thaver 
and  Hewetson,  "The  Malarial  Fevers  of  Baltimore,"  Baltimore,  1895,  p.  58.) 

oc-  ctL  4  Johns  Hopkins  Hosp.  Bull.,  1894,  vol.  v,  p.  89. 


47° 


GENERAL  HEMATOLOGY. 


examinations,  100  in  number,  show  that  the  number  of  leucocytes 
averaged  4323  per  c.mm.,  or  a  decrease  of  about  38  per  cent, 
below  normal.  In  71  counts  made  by  this  reporter  in  16  cases, 
to  determine  the  effects  of  the  malarial  paroxysms  on  these 
cells,  it  was  found  that  during  the  early  part  of  the  paroxysm  their 
number  gradually  increased,  the  maximum  being  reached,  as  a 
rule,  two  or  three  hours  after  the  chill.  Following  this  maximum 
increase  the  number  steadily  and  progressively  decreased,  hour  by 
hour,  until  the  minimum  was  reached  during  the  period  of  sub- 
normal temperature,  at  the  end  of  the  paroxysm.  During  the 
afebrile  interval  the  number  of  leucocytes  is  distinctly  subnormal, 
but  it  rises  slightly  again  just  before  the  onset  of  the  following  chill, 
so  that  the  average  count  is  slightly  higher  immediately  before  the 
chill  than  during  the  rest  of  the  interval. 

In  the  author's  series,  above  referred  to,  the  average  of  45 
counts  showed  5622  leucocytes  per  c.mm.,  the  lowest  count  being 
2000,  and  the  highest  i2,8po.  All  these  counts  were  made  during 
the  interval  between  the  paroxysms,  in  uncomplicated  cases,  so 
far  as  it  was  possible  to  determine. 

The  counts  ranged  as  follows: 

Leucocytes  per  c.mm.  Number  of  Cases. 

Above  10,000   3 

Between  8,000-10,000   9 

"      6,000-  8,000   9 

"      4,000-  6,000  10 

"      2,000-  4,000  14 

Average,       5,622  per  c.mm. 

Maximum,  12,800  "  " 

Minimum,    2,000  "  " 

In  the]7  cases  of  "malarial  cachexia"  the  number  of  leucocytes 
to  the  c.mm.  ranged  from  4500  to  44,000,  the  average  being  16,971. 
Five  of  these  cases  had  distinct  leucocytosis,  a  condition  believed 
by  Thayer  to  occur  in  some  of  the  post-malarial  anemias,  usually 
those  following  short-lived  infections. 

Relative  lymphocytosis,  sufficiently  decided  to  become  a  striking 
characteristic  of  the  condition,  is  practically  a  constant  qualitative 
change.  As  a  rule,  the  increase  affects  chiefly  the  large  lympho- 
cytes. Christophers  and  Stephens,1  in  a  study  of  "blackwater 
fever,"  found  that  this  type  of  cells  often  constituted  20  per  cent., 
30  per  cent.,  or  even  50  per  cent,  of  the  total  number  of  leucocytes; 
furthermore,  they  state  that  this  relative  increase  bears  an  inverse 
relation  to  the  temperature  curve,  being  least  marked  during  the 

1  Lancet,  1901,  vol.  i,  p.  848. 


MALARIAL  FEVER. 


pyrexia  and  greatest  during  the  periods  of  apyrexia.  This  feature 
of  the  blood  picture,  which  is  of  considerable  importance,  has 
also  been  noted  by  Delany,1  by  Rogers,2  and  by  Daniels.3  The 
percentage  of  eosinophiles  is,  as  a  rule,  subnormal,  and  this  variety 
of  cells  is  frequently  absent ;  more  rarely  they  are  slightly  increased, 
especially  in  some  of  the  post-malarial  anemias.  Myelocytes  in 
small  numbers  are  very  commonly  found,  in  the  writer's  experience, 
especially  in  estivo-autumnal  infections  and  in  cases  with  pro- 
nounced anemia.  In  9  differential  counts,  made  in  cases  of  the 
series  above  referred  to,  the  relative  percentages  of  the  different 
forms  of  leucocytes  averaged  as  follows: 

Small  lymphocytes  15.33  Per  cent- 

Large  lymphocytes   and  transitional 

forms  15.94  " 

Polynuclear  neutrophiles  67.00  " 

Eosinophiles   0.83  " 

Myelocytes   0.51  " 

Practically  the  same  figures  were  obtained  from  the  similar  ex- 
amination of  5  cases  of  anemia  associated  with  malarial  cachectic 
conditions. 

The  blood  plaques  are  greatly  decreased  in  number,  as  in  other 
febrile  conditions.  They  fail  to  agglutinate  in  both  tertain  and 
quartan  fevers,  according  to  Zeri  and  Almazia,4  unless  cinchoni- 
zation  is  pushed  sufficiently  to  antidote  the  infection.  In  normal 
blood  and  in  the  blood  of  various  non-malarial  fevers  the  plaques 
clump  together  in  masses  just  before  and  during  the  process  of 
clotting.  Ducchesi's  method  may  be  used  to  show  this  phenom- 
enon macroscopically.    (See  p.  199.) 

The  detection  of  the  specific  parasite  in  the 

Diagnosis,  circulating  blood  is  proof  positive  of  malarial 
fever,  the  exact  type  of  which  may  be  determined 
by  close  study  of  the  organism's  peculiarities.  Even  if  nothing 
more  definite  than  pigmented  leucocytes  is  found,  the  evidence 
is  strongly  in  favor  of  some  form  of  paludism.  The  progressive 
anemia  and  the  leucopenia  involving  a  relative  decrease  in  the 
polynuclear  neutrophiles  are  also  valuable  side-lights  on  the 
diagnosis.  An  obscure  intermittent  fever  which  shows  leucocy- 
tosis  is  almost  certainly  not  malarious. 

The  chills  and  pyrexia  of  sepsis  and  of  tuberculosis  are  not  in- 

1  Brit.  Med.  Jour.,  1903,  vol.  i,  p.  725.  ) 

2  Ibid.,  1902,  vol.  i,  p.  827;  also  Lancet,  1903,  vol.  i,  p.  1500. 

3  Cited  by  Manson,  Lancet,  1902,  vol.  i,  p.  1377. 
4 II  Policlin.,  1903,  vol.  ix,  p.  485. 


472 


GENKRAL  HEMATOLOGY. 


frequently  misinterpreted  as  symptoms  of  malarial  fever.  In 
septicemia  leucocytosis  is  usually  found,  but  even  should  the 
leucocytes  not  be  increased  in  number,  they  fail  to  show  the 
relative  lymphocytosis  of  malarial  blood.  In  pure  tuberculosis 
the  blood  picture  of  malaria  may  be  counterfeited,  in  so  far  as  the 
quantitative  and  qualitative  leucocyte  changes  are  concerned,  and 
in  such  instances  the  parasite  must  be  demonstrated  to  settle  the 
diagnosis. 

Enteric  fever,  like  malaria,  shows  anemia,  an  absence  of  leuco- 
cytosis, and  relative  mononucleosis.  But  in  typhoid  the  small 
lymphocytes  are  increased,  while  in  malaria  the  large  mononuclear 
forms  are  in  excess.  Minor  points  of  difference  are  the  more 
rapid  onset  of  the  anemia,  the  greater  frequency  of  decided  leuco- 
penia,  and  the  tendency  toward  higher  percentages  of  myelocytes 
in  malaria.  The  pertinence  of  positive  examinations  for  the 
specific  parasite  and  for  the  serum  reaction  is  obvious.  It  may  be 
added  that  in  those  rare  instances  of  coincident  typhoid  and  malaria 
the  blood  of  the  same  individual  may  contain  malarial  parasites 
and  give  a  positive  serum  reaction  with  the  Eberth  bacillus.  In 
such  cases  blood  cultures  prove  the  presence  of  the  typhoid  in- 
fection. V 

XLIV.  MALIGNANT  DISEASE. 

Carcinoma. 

There  is  no  deviation  from  normal  in  the 
General     coagulability  and  the  amount  of  fibrin,  except  in 
Features,     the  event  of  ulcerative  and  inflammatory  changes 
affecting  the  tumor,  but,  should  these  conditions 
be  present,  coagulation  may  occur  with  abnormal  rapidity,  and 
the  density  of  the  fibrin  network  almost  invariably  increases. 
The  specific  gravity  may  or  may  not  be  subnormal,  according  to 
whether  or  not  the  percentage  of  hemoglobin,  which  it  parallels, 
is  reduced.    The  alkalinity  of  the  blood  is  almost  always  decreased 
in  gastric  cancer,  according  to  Krokiewicz.1 

Relatively  large  amounts  of  sugar  (as  high  as  3  parts  per 
1000)  have  been  found  in  the  blood  of  patients  suffering  from 
various  forms  of  carcinoma,  especially  visceral  cancer,  in  contra- 
distinction to  more  superficial  growths,  involving,  for  example,  the 
skin  and  mucous  membranes.  In  no  other  disease  except  diabetes 
has  more  than  one-third  of  the  above-named  quantity  of  sugar  been 
detected  in  the  blood,  according  to  the  analyses  made  by  Trinkler.2 

1  Arch.  f.  Verdauungskr.,  1900,  vol.  vi,  p.  25. 

2  Centralbl.  f.  d.  med.  Wissensch.,  1890,  vol.  xxviii,  p.  498. 


MALIGNANT  DISEASE. 


473 


Examination  of  the  blood  for  the  detection  of  a  specific  parasite 
of  cancer  has  thus  far  proved  unconvincing,  although  much  care- 
ful work  has  been  done  with  this  purpose  in  view.  None  of  the 
many  bacteria  exploited  as  the  cause  of  cancer  has  fulfilled  Koch's 
law,  and  many  of  them  have  been  shown  to  be  artefacts.  The 
protozoan  theory  of  cancer,  defended  chiefly  by  Ruffner,1  Gaylord,2 
and  Feinberg,3  has  been  criticized  on  the  grounds  that  the  so-called 
protozoa  found  in  the  neoplasms  are  nothing  more  than  cell  in- 
clusions and  degenerations.  The  same  stricture  has  been  urged 
against  the  theory  advocated  by  Russell,4  Sanfelice,5  and  Plimmer,6 
who  interpret  the  factor  of  cancer  as  a  yeast  fungus.  The  careful 
studies  of  33  cases  of  cancer  by  Maragliano7  have  apparently  dis- 
proved the  statements  of  a  number  of  authors,  who  claimed  to  have 
cultivated  blastomycetes  from  the  circulating  blood  in  this  disease. 

During  its  incipiency  carcinoma  gives  rise  to 
Hemoglobin  practically  no  changes  in  the  erythrocytes  or  their 
and         hemoglobin  content,  or,  at  the  most,  causes  simply 
Erythrocytes,  a  moderate  diminution  in  the  latter.    As  the 
disease  progresses   and   extends,   and   as  the 
cachexia  of  the  patient  becomes  more  pronounced,  a  secondary 
anemia   develops, *  attaining   but  a  moderate  degree  in  some 
instances,  but  in  others  becoming  so  extreme  as  to  simulate  in 
some  particulars  true  pernicious  anemia.    The  anemia  of  cancer 
differs  from  other  forms  of  secondary  anemia  in  stubbornly 
persisting,  or  at  the  most  improving  but  slightly,  under  treatment. 
Since  the  hemoglobin  loss  usually  anticipates  the  cellular  decrease, 
the  blood  picture  of  early  cancer  not  infrequently  resembles  that 
of  chlorosis.    Later,  however,  these  conditions  may  be  reversed, 
so  that  the  index  rises.    In  the  author's  experience,  the  average 
hemoglobin  loss  has  amounted  to  about  33  per  cent.,  and  the 
erythrocyte  decrease  to  about  22  per  cent.,  of  normal.  The  color 
index  tends  to  range  moderately  below  normal,  usually  from 
20  to  30  points  below  the  standard  of  health.    It  averaged  0.86  for 
the  145  cases  grouped  below.    As  just  intimated,  it  is  generally 
lower  in  the  early  than  in  the  late  stages  of  the  disease.    In  oper- 
ative cases  of  carcinoma  it  has  been  observed  that  the  regeneration 
time  of  the  hemoglobin  averages  at  least  two-thirds  longer  than  in 

1  "Sur  les  Parasites  des  Tumeurs  Epitheliales  Malignes,"  1896. 

2  Amer.  Jour.  Med.  Sci.,  1901,  vol.  cxxi,  p.  503. 

3  "  Das  Gewebe  und  die  Ursache  der  Krebsgeschwiilste,"  1903. 

4  Brit.  Med.  Jour.,  1900,  vol.  ii,  p.  1356. 

5Zeitschr.  f.  Hyg.  u.  Infektionskr.,  1898,  vol.  xxix,  p.  463. 

6  Practitioner,  1899,  vol.  lxvii,  p.  430. 

7  Gaz.  degli  Ospedali  e.  d.  Clin.,  i9oo,  vol.  xxi,  p.  1538;  also  Sem.  meU,  1901, 
vol.  xxi,  p.  63. 


474 


GENERAL  HEMATOLOGY. 


other  diseases  treated  surgically,  and  that  the  loss  of  hemoglobin 
after  operation  is  usually  not  less  than  15  per  cent.  Bierfreund1 
finds  that  the  percentage  of  hemoglobin  after  the  removal  of  the 
tumor  never  equals  that  found  before  the  operation. 

The  oligocythemia  is  occasionally  most  striking,  for  in  some 
cases  the  counts  may  range  as  low  as  between  1,000,000  and 
2,000,000,  such  a  degree  of  decrease  apparently  being  most  com- 
monly found  in  septic  cases  and  in  gastric  cancer.  F.  P.  Henry's 
statement2  that  he  has  never  seen  a  case  of  the  latter  disease  in 
which  the  erythrocytes  fell  below  1,500,000  to  the  c.mm.  has  been 
generally  corroborated,  although  counts  below  this  figure  have  been 
occasionally  reported.  In  one  of  the  cases  of  cancer  of  the  stomach 
included  in  the  table  given  below  the  count  was  1,001,000  per 
c.mm.,  and  the  hemoglobin  percentage  50;  in  another  case  the 
count  was  1,240,000  and  the  hemoglobin  56  per  cent. 

Polycythemia  may  occur  as  a  temporary  condition  in  gastric 
and  esophageal  cancer,  as  the  result  of  blood  concentration  due 
to  vomiting,  to  diarrhea,  or  to  lack  of  ingested  fluids.  In  such 
instances  the  number  of  erythrocytes  not  uncommonly  exceeds 
6,000,000  or  7,000,000  per  c.mm.,  and,  exceptionally,  even  a 
higher  figure. 

The  following  table  illustrates  the  alterations  in  the  amount 
of  hemoglobin  and  number  of  erythrocytes,  as  determined  by 
the  examination  of  145  cases  of  various  forms  of  carcinoma: 

Hemoglobin   Number  of  Erythrocytes  Number  of 

Percentage.      Cases.  per  c.mm.  Cases. 

From  90-100  5  Above  5,000,000  13 

"    80-  90  30  From  4,000,000-5,000,000  ..66 

"     70-  80  32  "     3,000,000-4,000,000  ..39 

29  "     2,000,000-3,000,000  ..18 

21  "     1,000,000-2,000,000  9 


60-  70. . . 
50-  60. . . 
40-  50... 
30-  40... 
20-  30. . . 


12 
10 
4 


10-  20  2 

Average,    67.0  per  cent.  Average,     3,897,923  per  c.mm. 

Maximum,  94.0  "     "  Maximum,  5,900,000   "  " 

Minimum,  12.0  "     "  Minimum,  1,001,000  "  " 

In  gastric  cancer  Osier  and  McCrae3  report  an  average  of  49.9 
per  cent,  of  hemoglobin  in  52  cases,  and  an  average  erythrocyte 

1  Langenbeck's  Arch.,  1890-91,  vol.  xli,  p.  1. 

2  Arch.  f.  Verdauungskr.,  1898,  vol.  iv,  p.  1. 

3  "Cancer  of  the  Stomach,"  London  and  Philadelphia,  1900,  p.  115. 


MALIGNANT  DISEASE. 


475 


count  of  3,712,186  in  59  cases.  In  two  cases  the  count  was  less 
than  1,500,000.  An  average  color  index  of  0.63  was  found  in 
this  series.  The  author,  in  a  series  of  46  cases,  found  the  anemia 
less  decided,  as  shown  by  these  averages:  hemoglobin,  67.5  per 
cent;  erythrocytes,  4,020,978;  color  index,  0.84.  Lang1  finds  that 
the  isotonicity  of  the  erythrocytes  is  increased  in  this  disease, 
and  this  change  he  attributes  to  the  organism's  attempt  to 
combat  some  obscure  hemolytic  agent  peculiar  to  the  cancerous 
process, 

Deformities  of  shape  and  of  size  are  marked  in  relation  to  the 
grade  of  the  anemia  which  exists.  Poikilocytes  may  be  quite  as 
numerous  and  as  striking  as  in  true  pernicious  anemia,  while  the 
alterations  affecting  simply  the  size  of  the  cells  tend  toward  micro- 
cytosis  rather  than  megalocytosis.  Polychromatophilia  and  baso- 
philic degenerative  changes  are  frequently  to  be  seen  in  grave 
cases  with  marked  cachexia. 

Erythroblasts  are  very  common,  especially  in  cancer  with 
decided  cachexia  and  high-grade  anemia,  but  their  occurrence  is 
by  no  means  limited  to  such  cases,  as  they  may  also  be  found  in 
blood  which  shows  but  trifling  quantitative  deterioration.  It  may 
be  stated  as  an  accepted  fact  that  nucleated  erythrocytes  occur  in 
cancer  more  frequently  than  in _any  other  variety  of  sej:onjiary„ 
anemia,  except  that  accompanying  sarcoma. 

Normoblasts  are  generally  found  to  the  exclusion  of  other 
forms,  although  in  an  exceptionally  grave  case  an  occasional 
megaloblast  and  atypical  "mesoblast"  may  be  encountered.  The 
important  point  to  be  remembered  is  that  cells  of  the  adult,  normo- 
blastic type  invariably  predominate,  since  megaloblasts,  when 
present,  are  never  so  numerous  as  normoblasts. 

Leucocytosis  is  a  frequent  but  not  a  constant 
Leucocytes,  feature  of  the  blood  picture  in  carcinosis,  for 
more  cases  are  encountered  in  which  the  number 
of  leucocytes  is  normal  than  those  in  which  an  increase  prevails. 
Judging  from  the  statistics  of  patients  treated  in  the  German  Hos- 
pital, leucocytosis  is  present  in  less  than  one-third  of  all  forms 
of  cancer,  or  in  31  per  cent.  In  general  terms,  it  may  be  said 
that  tumors  characterized  by  active  inflammatory  changes,  by 
hemorrhage,  by  rapid  growth,  or  by  extensive  metastases  are 
accompanied  by  a  well-marked  leucocyte  increase,  while  non- 
inflammatory, slowly  developing,  localized  tumors  do  not  raise 
the  count.  Thus,  a  large  carcinoma  of  the  liver  or  kidney,  for 
instance,  may  cause  a  leucocytosis  of  30,000  or  40,000  to  the  c.mm., 
while  a  small,  limited  skin  cancer  may  exist  without  provoking 

1  Zeitschr.  f.  klin.  Med.,  1902,  vol.  xlvii,  p.  153. 


476 


GENERAL  HEMATOLOGY. 


the  slightest  increase.  Thorough  extirpation  of  the  growth  is 
followed  by  a  decline  in  the  leucocytosis,  the  normal  count  being 
reached  by  the  time  the  wound  has  entirely  healed.  Hayem1  is 
the  authority  for  the  statement  that  in  mammary  cancer  recurrence 
of  the  growth  after  its  removal  may  be  detected  by  a  reappearance 
of  the  leucocytosis,  which  antedates  all  other  physical  signs.  The 
constancy  of  this  change,  as  well  as  the  question  of  its  occurrence 
in  cancer  involving  other  structures,  still  remains  to  be  investigated. 

It  seems  reasonable  to  attribute  the  origin  of  cancer  leucocy- 
tosis chiefly  to  the  presence  of  inflammatory  changes  and  to  hemor- 
rhage in  the  tissues  in  the  neighborhood  of  the  growth,  although 
in  some  instances  it  seems  possible  that  positive  chemotaxis  may 
be  excited  by  the  absorption  of  toxins  derived  from  the  breaking 
down  of  the  neoplasm  itself.  The  strength  of  the  patient's  powers 
of  resistance  as  a  determining  factor  of  the  increase  must  also  be 
taken  into  account  in  this  as  in  other  diseases. 

In  the  writer's  experience,  leucocytosis  is  most  constant  and 
most  striking  in  cancer  of  the  liver,  least  frequent  in  cancer  of 
the  uterus,  and  least  conspicuous  in  cancer  of  the  stomach.  In 
cancer  of  the  esophagus  absence  of  leucocytosis  is  the  rule,  while 
in  many  cases  a  decided  leucopenia  may  exist.  Skin  cancers, 
unless  ulcerated  and  inflamed,  do  not  raise  the  count. 

The  145  cases  on  the  study  of  which  the  above  observations 
are  based  may  be  summarized  as  follows : 


Seat  of 
Growth. 


Number  and  Percentage 
of  Cases  with  Leucocytosis. 


Stomach . 
Uterus  . . 
Rectum  . 
Breast  . . 
Liver  . . . 
Bowel  . . 
Pancreas 


69 


22 


10 


15 
18 


7 
4 


17  or  24.6  per  cent. 

3  "  13-6  " 

4  "  26.6  " 


8  "  80.0 


2 


(t 


71.4 
50.0 


7,858 
11,225 

9,650 
10,163 

17,549 
II,l85 
10,850 


23,400 
24,000 
l6,000 

31, 5°° 
40,800 
16,300 
18,200 


1,000 
3,200 
6,000 
5,200 
8,000 
7,000 
6,660 


As  compared  with  the  above,  this  summary  of  Cunliffe's  71 
cases2  shows  a  decidedly  higher  leucocyte  average  and  range: 

1  Loc.  cit.  2  Med.  Chronicle,  1903,  vol.  xxxviii,  p.  333. 


MALIGNANT  DISEASE. 


477 


Si  \  i   OF  G  row  ni. 


Stomach . 
Uterus. . . 
Rectum . . 
Breast. . . 
Esophagu 
Tongue. . 


Number  of 

Average 

Maximum 

Minimum 

Casks. 

Count. 

Count. 

Count. 

io 

17,280 

36,800 

5-200 

8 

22,8oO 

59,200 

7.000 

IO 

12,780 

20,200 

6,800 

18 

11,400 

24,800 

7,800 

13 

13,700 

30,800 

10,000 

12 

13,400 

24,800 

7;8oo 

In  cancer  of  the  stomach  digestion  leucocytosis  is  usually, 
though  by  no  means  invariably,  absent.  The  frequency  with 
which  this  phenomenon  is  absent  is  shown  by  the  following  com- 
pilation of  the  data  of  various  authorities  who  have  studied  this 
question  : 


Author. 


Hoffman  

Osier  and  McCrae 

Cabot  

Schneyer  

Capps  

Krokiewicz  

Douglas  

Hartung  

Muller  


Number 
of  Cases. 

Absent. 

Present 

24 

21 

3 

22 

12 

10 

20 

19 

1 

18 

18 

0 

17 

15 

2 

17 

13 

4 

II 

6 

5 

10 

10 

0 

5 

5 

0 

144 

119 

25 

These  figures,  referring  to  144  cases,  show  that  digestion  leu- 
cocytosis is  absent  in  82.6  per  cent,  of  gastric  carcinomata.  But 
the  presence  of  the  phenomenon  in  practically  one  case  out  of 
five  is  sufficient  to  weaken  materially  the  former  belief  that  ab- 
sence of  digestion  leucocytosis  is  a  diagnostic  sign  of  this  disease. 
Furthermore,  it  has  also  been  shown  by  Hoffman  1  and  others 
that  the  sign  may  be  absent  in  a  number  of  other  diseases  of  the 
stomach,  as  well  as  in  some  apparently  healthy  individuals. 

Rencki,2  from  an  investigation  of  15  cases,  concludes  that  the 
digestion  leucocytosis  of  gastric  cancer,  when  present,  averages 
an  increase  of  3500  cells,  and  that  this  acme  is. reached  the  third 
or  fourth  hour  after  taking  food. 

Differential  counts  usually  show  percentages  of  polynuclear 
neutrophiles  ranging  between  80  and  90,  with  a  corresponding 
decrease  in  the  large  and  small  lymphocytes,  in  cases  with  leu- 
cocytosis, and  not  infrequently  also  in  those  without.  This 

1  Zeitschr.  f.  klin.  Med.,  1898,  vol.  xxxiii,  p.  460. 

2  Arch.  f.  Verdauungskr.,  1901,  vol.  vii,  pp.  234  and  392. 


478 


GENERAL  HEMATOLOGY. 


change  is  not  to  be  considered  constant,  since  relatively  high 
percentages  of  lymphocytes,  especially  of  the  large  variety,  have 
occasionally  been  observed.  The  eosinophiles  are  usually  de- 
creased, or,  indeed,  they  may  be  absent  in  cases  with  pronounced 
leucocytosis;  in  a  certain  proportion  of  cases,  in  spite  of  the  ab- 
normally high  leucocyte  count,  their  relative  percentage  remains 
within  the  limits  of  health.  Myelocytes  are  extremely  common, 
small  numbers  of  these  cells  (usually  not  higher  than  a  fraction 
of  one  per  cent.)  occurring  in  at  least  a  majority  of  all  cases  of 
cancer.  In  cancer  with  bone  metastases  these  cells  are  much 
more  abundant.  (See  p.  259.)  The  presence  of  a  few  basophiles 
is  sometimes  to  be  noted,  particularly  often  in  association  with 
conspicuously  high  leucocytoses. 

Sarcoma. 

The  changes  affecting  the  fibrin,  the  rate  of 
General  coagulation,  and  the  specific  gravity  of  the  blood 
Features,     are  similar  to  those  prevailing  in  cancer,  and 

therefore  require  no  further  mention. 
In  contrast  to  the  hyperglycemia  of  carcinoma,  the  researches 
of  Trinkler,  previously  referred  to,  tend  to  show  that  in  sarcoma 
no  increase  above  normal  in  the  amount  of  sugar  in  the  blood  can 
be  detected.  Bacteriological  examinations  of  the  blood  have  thus 
far  given  no  definite  results. 

Loeper  and  Louste  1  report  having  found  sarcoma  cells  in  the 
blood  of  three  cases  of  sarcoma,  one  affecting  the  neck,  one  the 
shoulder,  and  one  being  a  general  sarcomatosis.  These  observers 
centrifugalized  a  mixture  of  20  drops  of  finger  blood  and  15  c.c. 
of  a  one  per  cent,  aqueous  solution  of  acetic  acid,  and  detected 
in  the  resulting  sediment  cells  precisely  similar  in  morphology  and 
other  biological  characteristics  to  those  of  the  neoplasms  in  ques- 
tion. In  carcinoma,  on  the  contrary,  specific  cytological  findings 
in  the  blood  were  absent.  These  experiments,  if  substantiated, 
should  be  of  signal  value  in  the  diagnosis  of  deep-seated  sarcomata. 
They  tend  also  to  corroborate  the  belief  that  sarcoma,  but  not 
cancer,  spreads  by  the  blood  stream. 

The  changes  in  the  hemoglobin  and  erythro- 
Hemoglobin  cytes  are  not  materially  different  from  those  found 
and         in  cancer,  for  the  genesis  of  the  blood  deteriora- 
Erythrocytes.  tion  is  doubtless  similar  in  all  forms  of  malignant 
disease.    Some  authors  believe  that  the  anemia 
tends  to  reach  a  higher  degree  in  sarcoma  than  in  carcinoma, 
but  the  truth  of  this  contention  certainly  does  not  appear  to  be 
1  Sem.  med.,  1904.  vol.  xxiv,  p.  36. 


MALIGNANT  DISEASE. 


479 


indisputably  established.  In  the  writer's  experience,  the  intensity 
of  the  anemia  is  practically  similar  in  both  these  forms  of  neo- 
plasms, or,  if  anything,  somewhat  more  striking  in  cancer,  both 
individually  and  on  the  average.  In  a  series  of  34  cases  of  sarcoma 
the  following  data  were  obtained: 

Hemoglobin  Number  of      Erythrocytes  Number  of 

Percentage.  Cases.  per  c.mm.  Cases. 

Above  100  1  Above  5,000,000    5 

From  90-100  1  From  4,000,000-5,000,000.-13 

80-90  8  "     3,000,000-4,000,000 . .  1 2 

70-80  6  "      2,000,000-3,000,000..  3 

60-70  6  "      1,000,000-2,000,000..  1 

50-60  6 

40-50  4 

30-40  1 

20-30  1 

Average,     65.5  per  cent.  Average,     3,962,705  per  c.mm. 

Maximum,  101  Maximum,  5,400,000  "  " 

Minimum,     25  Minimum,  1,400,000  "  " 

Poikilocytes,  microcytes,  megalocytes  and  atypically  stained 
cells  are  common  in  cases  with  pronounced  anemia,  and  in  such 
instances  erythroblasts,  the  majority  of  which  are  always  normo- 
blasts, are  also  to  be  looked  for. 

Leucocytosis,  while  inconstant  in  sarcoma,  is 
Leucocytes,  without  doubt  more  frequently  associated  with 
this  lesion  than  with  carcinoma.  Statistics  have 
also  been  advanced  to  demonstrate  that  the  counts  range  higher 
than  in  cancer,  but  the  cases  on  record  are  still  far  too  few  to 
warrant  this  conclusion.  The  behavior  of  the  leucocytes  in  both 
forms  of  malignant  disease  is  probably  influenced  by  the  same 
group  of  factors.  In  the  cases  summarized  in  this  series,  leuco- 
cytosis was  found  in  45  of  the  145  carcinomata,  or  in  31  per 
cent.,  and  in  20  of  the  34  sarcomata,  or  in  58.8  per  cent.  In  the 
latter  the  counts  varied  as  follows : 

Leucocytes  per  c.mm.  Number  of  Cases. 

From  30,000-40,000   1 

"    20,000-30,000   2 

"    15,000-20,000   5 

"    10,000-15,000  ..13 

"      5,000-10,000  13 

Average,     12,282  per  c.mm. 

Maximum,  40,000  "  " 

Minimum,    5,000  "  " 


480 


G E NERAL  II E MATO LOG Y . 


The  increase  usually  involves  a  large  absolute  and  relative 
gain  in  the  polynu clear  neutrophiles  at  the  expense  of  the  lympho- 
cytes, although  in  an  occasional  instance  the  latter  reach  a  dispro- 
portionately high  percentage,  while  the  former  decline  to  a  sub- 
normal figure.  It  may  be  added  that  either  of  these  differential 
changes  may  also  occur  in  the  absence  of  an  increase  in  the  total 
number  of  leucocytes.  The  percentage  of  eosinophils  is  usualry 
subnormal,  and  not  infrequently  these  cells  may  be  searched  for 
in  vain.  Rarely,  marked  eosinophilia  has  been  reported  in  sar- 
comata with  bone  metastases,  but  such  findings  are  by  no  means 
constant.  Decided  myelemia  (as  high  as  10  or  15  per  cent.), 
according  to  Kurpjuweit,1  may  develop  as  the  result  of  the  altered 
hemogenesis  excited  by  invasion  of  the  bone  marrow  by  malignant 
tumors.  In  all  forms  of  sarcoma  small  numbers  of  myelocytes  are 
to  be  observed  a^  frequently  as  not,  these  cells  being  about  as 
common  and  as  numerous  as  they  are  in  cancer — a  remark  which 
is  also  true  of  basophiles. 

The  clinical  resemblance  between  certain 

Diagnosis,  forms  of  malignant  disease  (especially  those  in 
which  the  lesion  remains  obscure  or  undemon- 
strable)  and  pernicious  anemia  is  often  very  close,  on  account  of 
the  striking  degree  of  cachexia  apparent  in  both.  But  the  blood 
changes  found  in  these  two  conditions,  although  similar  in  some 
respects,  are  sufficiently  characteristic  to  afford  the  necessary 
diagnostic  clue.  These  differences,  already  referred  to  in  a  pre- 
ceding section,  may,  for  the  sake  of  emphasis,  be  expressed  as 
follows : 


Malignant  Disease. 
Color  index  usually  moderately 
low. 

Oligocythemia  usually  marked. 

Tendency  toward  microcytosis. 

Erythroblasts  common,  normo- 
blasts always  predominating. 

Leucocytosis  common. 
Lymphocytosis  rare. 


Pernicious  Anemia. 
Color    index    almost  always 
high. 

Oligocythemia  invariably  ex- 
treme. 

Tendency  toward  megalocy- 
tosis. 

Erythroblasts  constant,  mega- 
loblasts  always  predominat- 
ing. 

Leucocytosis  rare. 
Lymphocytosis  common. 


It  is  to  be  noted  that  of  the  above  changes,  but  one  is  charac- 
teristic—the invariable  predominance  of  megaloblastic  cells  in 

1  Deutsch.  Arch.  f.  klin.  Med.,  1903,  vol.  lxxvii,  p  .  553. 


MALIGNANT  DISEASE. 


481 


pernicious  anemia  and  their  minority  or  absence  in  those  cases  of 
malignant  disease  in  which  nucleated  erythrocytes  are  found. 

Should  a  doubt  arise  as  to  whether  a  tumor  is  benign  or  malig- 
nant in  character,  the  fact  is  to  be  remembered  that  the  presence 
of  a  persistent  leucocytosis,  especially  if  accompanied  by  anemia, 
is  decidedly  in  favor  of  its  malignancy.  Should  it  be  necessary 
to  distinguish  between  a  malignant  growth  and  an  obscure  pus 
focus  with  sepsis,  the  blood  examination,  aside  from  culturing,  is 
useless,  since  both  leucocytosis  and  hyperinosis  may  or  may  not 
exist  m  either  condition;  if,  however,  bacteriological  findings  are 
positive,  the  existence  of  a  septicemia  is  obvious. 

As  a  means  of  differentiating  carcinomata  and  sarcomata,  the 
chemical  examination  of  the  blood  for  sugar  should  prove  of  the 
greatest  clinical  value,  if  further  research  substantiates  the  claims 
made  that  hyperglycemia  is  constant  in  the  first,  and  absent  in 
the  second,  type  of  neoplasms. 

As  a  means  of  distinguishing  gastric  cancer  from  gastric  ulcer 
the  blood  count  is,  unfortunately,  of  doubtful  utility.  The  pres- 
ence of  a  persistent,  well-marked  leucocytosis  is  a  very  significant 
sign  of  cancer,  since  in  ulcer  the  count  is  not  increased  except 
as  the  result  of  hemorrhage,  perforation,  or  digestion.  On  the 
other  hand,  an  absence  of  leucocytosis  is  of  no  value  in  determin- 
ing which  condition  is  present,  owing  to  the  fact  that  no  increase 
occurs  in  a  large  proportion  of  stomach  cancers.  Tuffier,1  who 
found  that  tumors  of  epithelial  origin  cause  mononucleosis,  con- 
tends that  it  is  possible  by  this  sign  to  differentiate  gastric  cancer 
and  ulcer.  This  observation  was  not  confirmed  by  Monisset  and 
Tolot,2  whose  studies  show  that  it  is  impossible  to  take  the  differ- 
ential count  as  a  criterion  of  diagnosis.  Recent  investigations 
have  fully  corroborated  Lowit's  view  that  the  absence  of  diges- 
tion leucocytosis  in  gastric  cancer  has  about  the  same  diagnostic 
value  as  the  absence  of  hydrochloric  acid  and  the  presence  of  lactic 
acid. 

_  The  chief  points  of  distinction  in  the  blood  pictures  associated 
with  the  two  diseases  in  question  are  illustrated  by  this  table: 


Gastric  Cancer. 
Anemia  usually  marked. 
Erythroblasts  common. 
Leucocytosis  common. 
Absence  of  digestion  leucocy- 
tosis the  rule. 

1  Presse  med.,  1901,  vol.  viii,  p.  246. 
3i 


Gastric  Ulcer. 

Anemia  usually  moderate,  ex- 
cept after  hemorrhage. 

Erythroblasts  rare. 

Leucocytosis  rare. 

Absence  of  digestion  leucocy- 
tosis the  exception. 

2  Rev.  de  med.,  1902,  vol.  xxii,  p.  844. 


482 


GENERAL  HEMATOLOGY. 


If  the  diagnosis  lies  between  carcinoma,  amyloid  disease,  and 
gumma  of  the  liver,  the  presence  of  a  leucocytosis  suggests  the 
first;  should  it  lie  between  cancer  and  hypertrophic  cirrhosis  of 
the  liver,  high  leucocytosis  (30,000  or  more)  is  strongly  in  favor 
of  the  first,  since  although  the  leucocytes  may  be  increased  moder- 
ately in  this  variety  of  cirrhosis,  they  do  not  reach  a  strikingly 
high  figure.  In  an  instance  of  cancer  versus  echinococcus  cyst  of 
the  liver  a  high  eosinophilia  strongly  argues  the  latter  condition. 
Hyperinosis,  if  present,  is  also  a  sign  suggestive  of  cancer,  rather 
than  of  these  other  liver  diseases. 


XLV.  MALIGNANT  ENDOCARDITIS. 

The  blood  changes  in  malignant  or  ulcerative 
General     endocarditis  are  essentially  those  of  a  grave  sep- 
Features.     ticemia,  described  elsewhere,  and  do  not,  there- 
fore, require  extended  consideration  in  this  place. 
According  to  the  studies  of  Grawitz,1  Kraus,2  Sittman,3  Kuh- 
nau,4  James  and  Tuttle,5  Thayer  and  Lazear,6  and  others,  the 
chances  of  securing  definite  results  from  bacteriological  examina- 
tion of  the  blood  are  good  in  this  disease.    An  analysis  of  these 
authors'  work  shows  that  various  micro-organisms,  notably  pneu- 
mococci,  gonococci,  streptococci,  and  staphylococci,  are  demon- 
strable by  culture  of  the  peripheral  blood  with  great  frequency. 

The  loss  of  hemoglobin  and  erythrocytes  is 
Hemoglobin  likely  to  be  marked,  and,  in  acute  cases,  ex- 
and         tremely  rapid  and  often  most  excessive— some- 
Erythrocytes.  times  as  great  as  in  typical  pernicious  anemia. 

Structural  degenerative  changes  are  common,  as 
in  any  severe  anemia,  and  in  many  acute  cases  hemoglobinemia 
may  be  observed.  As  a  rule,  the  loss  of  hemoglobin  and  eryth- 
rocytes is  not  markedly  disproportionate,  so  that  moderately 
subnormal  color  indices  are  commonest. 

The  following  counts,  by  Dr.  Uhle,  of  a  profoundly  septic 
patient  at  the  German  Hospital,  illustrate  the  striking  degree  of 
anemia,  as  well  as  the  intermittent  and  moderate  leucocytosis 
which  may  develop  in  a  grave  case: 

1  Charite-Annal.,  1894,  vol.  xix,  p.  154. 

2  Zeitschr.  f.  Heilk.,  1896,  vol.  xvii,  p.  117. 

3  Deutsch.  Arch.  f.  klin.  Med.,  1894,  vol.  lm,  p.  323. 

4  Zeitschr.  f.  Hyg.  u.  Infektionskr.,  1897,  vol.  xxv,  p.  492-  ,  o  0  .  ... 
s  Med.  and  Surg.  Report  of  the  Presbyterian  Hosp,  New  York,  1898,  vol.  m, 

p.  44. 

8  Jour.  Exper.  Med.,  1899,  vol.  iv,  p.  81. 


MALIGNANT  ENDOCARDITIS. 


483 


Date. 


II-  4-99 
11-  8-99 
11-11-99 
11-16-99 
I 1-20-99 

11-  25-99 

12-  1-99 
12-  5-99, 
12-16-99. 
12-27-99. 

1-  5-00. 
1-11-00. 


Hkmoglobin 
Perckntage. 


30 
26 

3° 
28 

19 
24 

25 
35 

41 

36 
50 
38 


Erythrocytes. 

PER  C.MM. 


1,590,000 

8,000 

I  243,000 

8,400 

2,010,000 

12,800 

1,810,000 

8,000 

2,130,000 

14,000 

2,170,000 

12,800 

1,710,000 

9,600 

2,750,000 

16,000 

3,530,000 

7,200 

2,330,000 

4,800 

3,350,000 

8,000 

2,760,000 

4,000 

An  increase  in  the  number  of  leucocytes,  more 
Leucocytes,  commonly  moderate  than  marked,  and  character- 
ized  by  a  high  percentage  of  polynuclear  neutro- 
phils, is  the  usual  finding,  except  in  profoundly  septic  patients 
m  whom  the  count  may  be  normal  or  subnormal  during  the 
greater  part  of  the  illness,  as  shown  by  the  above  table.  Ab- 
sence of  leucocytosis  is  not  infrequent  in  this  disease,  doubtless 
because  m  a  large  proportion  of  cases  the  depressant  effects  of 
the  poison  predominate.  In  no  other  infection  is  a  better  illus- 
tration offered  of  the  relationship  between  the  behavior  of  the 
leucocytes,  the  intensity  of  the  disease,  and  the  patient's  powers 
ot  reaction.  Occasionally,  a  striking  preagonal  increase  develops, 
or,  on  the  contrary,  death  may  be  ushered  in  by  a  decided  leuco- 
penia. 

In  many  instances  the  diagnosis  of  malignant 
Diagnosis,    endocarditis  is  materially  facilitated  by  the  blood 
,       .  examination,  and  in  some  it  can  be  made  only 

by  this  means.  A  positive  result  from  blood  culturing  at  once 
gives  a  definite  clue  to  the  real  character  of  the  disease,  and  this 
procedure  should  be  undertaken  in  every  doubtful  case.  Malig- 
nant endocarditis  with  marked  constitutional  symptoms  is  perhaps 
most  frequently  confused  with  enteric  fever  and  occasionally  with 
malarial  fever.^  Both  of  these  infections  may  be  excluded  if  a  , 
eucocytosis  exists,  unless,  of  course,  this  sign  is  obviously  due 
to  some  complication.  It  should  also  be  remembered  that  in 
malignant  endocarditis  the  anemia  develops  early  and  tends  to 
attain  a  marked  degree  with  great  rapidity,  while  in  the  other  two 
levers  it  does  not  become  striking  until  the  post-febrile  stage  of 
the  disease  is  reached.  No  comment  is  necessary  on  the  value 
ot  obtaining  a  positive  serum  reaction  or  of  detecting  the  malarial 
parasite  as  a  means  of  distinguishing  this  trinity  of  infections. 


484 


GENERAL  HEMATOLOGY. 


XL VI.  MALTA  FEVER. 
Most  cases  are  accompanied  by  a  moderate,  progressive  second- 
ary anemia,  becoming  most  marked  at  about  the  end  of  the  febrile 
period,  and  involving,  according  to  Bruce,1  an  average  loss  of 
about  1,500,000  erythrocytes  to  the  c.mm.  The  most  severe 
anemia  is  found  in  cases  complicated  by  profuse  epistaxis  and  by 
hemorrhage  from  the  bowel,  but  those  in  which  these  symptoms 
are  absent  may  show  simply  a  slight  oligochromemia,  as  demon- 
strated by  a  case  studied  by  Musser  and  Sailer.2  Bassett-Smith3 
found  that  the  average  erythrocyte  loss  ranges  between  20  and  40 
per  cent,  below  the  normal  standard,  and  that  the  hemoglobin 
deficiency  is  relatively  greater.  In  severely  cachectic  patients  he 
noted  a  decided  increase  in  the  number  of  plaques,  together  with 
poikilocytosis,  a  tendency  toward  microcytosis,  but  never  nucleated 
erythrocytes.  This  observer  also  has  determined  that  the  pha- 
gocytic powers  of  the  leucocytes  are  diminished  and  the  bactericidal 
properties  of  the  blood  lowered  in  this  infection.  Frank  leucocy- 
tosis  does  not  develop,  except  as  the  result  of  hemorrhage,  but 
occasionally  the  number  of  leucocytes  is  slightly  increased— 
to  about  12,000  or  13,000  per  c.mm.  Charles4  states  that  during 
the  acute  stages  of  the  infection  he  has  found  a  notable  relative 
increase  in  the  large  lymphocytes.  In  Bassett-Smith's  cases  the 
percentage  of  mononuclear  leucocytes  ranged  from  26  to  76,  the 
polynuclear  neutrophiles  being  relatively  diminished.  Counts 
higher  than  6600  were  not  found. 

Bassett-Smith 5  cultured  the  Micrococcus  melitensis  from  the 
peripheral  blood  in  all  cases  during  the  early  stages  and  in  severe 
pyrexial  relapses,  thus  confirming  the  earlier  findings  of  Gilmour, 
Shaw,  and  Zammit.6  In  the  finger  blood  of  a  case  clinically 
identical  with  Malta  fever  Manson7  found  spirilla  similar  to,  yet 
differing  somewhat  from,  the  Spirillum  obermeieri.  Wright  and 
Smith8  found  that  the  blood  serum  of  patients  suffering  from 
Malta  fever  clumps  Bruce's  micrococcus  but  produces  no  aggluti- 
nation of  the  Bacillus  typhosus.  The  diagnostic  value  of  this 
serum  test  in  differentiating  Malta  and  enteric  fevers  has  since 
been  corroborated  by  the  reports  of  Aldridge,9  Musser  and 

1  Brit.  Med.  Jour.,  1889,  vol.  i,  p.  1101. 

2  Phila.  Med.  Jour.,  1898,  vol. .  ii,  p.  1408. 

3  Brit.  Med.  Jour.,  1902,  vol.  ii,  p.  861. 

4  Ibid.,  1898,  vol.  ii,  p.  607. 

5  Ibid..  1904,  vol.  ii,  p.  325. 

6  Cited  by  Bruce,  ibid.,  1904,  vol.  ii,  p.  323. 

7  Ibid.,  1904,  vol.  i,  p.  538.  -v  T7  . 7     00      1  • 

8  Lancet,  1897,  vol.  i,  p.  656.  8  Ibid.,  1898,  vol.  1,  p.  1394- 


MEASLES. 


485 


Sailer/  Krctz,2  Cox,3  Bassett-Smith,4  Craig,5  and  others.  A 
1:50  dilution  with  a  thirty-minute  time  limit  appears  to  give  the 
most  satisfactory  results,  but  in  many  instances  prompt  reactions 
occur  with  dilutions  of  from  1 : 100  to  1 :  250.    (See  p.  444.) 

XL VII.  MEASLES. 

The  amount  of  fibrin  is  either  normal  or  de- 
General     creased,  except  in  the  event  of  a  marked  inflam- 
Features.     matory  complication,  which  may  produce  hyper- 
inosis.    The  blood  plaques  are  decreased  in  num- 
ber during  the  febrile  period. 

A  peculiar  bacillus  has  been  isolated  from  the  blood  of  6  cases 
of  measles  by  Arsamaskoff,6  but  specificity  is  not  unreservedly 
claimed  for  it.  Zlatogoroff 7  has  also  cultured  a  novel  bacillus 
from  the  blood  in  17  of  24  cases,  the  organism  in  question  closely 
resembling  that  isolated  from  the  secretions  of  the  eye  and  nose. 
Protozoa  of  undetermined  character  have  been  detected  in  the 
blood  by  Weber.8 

The  hemoglobin  and  erythrocytes  are  prac- 
Hemoglobin  tically  unchanged  in  typical  cases.    When  a  de- 
and         crease  does  occur,  it  is  trifling,  amounting  at  the 
Erythrocytes,  most  to  a  loss  of  from  250,000  to  500,000  cor- 
puscles, and  of  about  15  or  20  per  cent,  of  hemo- 
globin.   The  great  majority  of  cases  have  counts  of  5,000,000 
cells  to  the  c.mm.    Qualitative  changes  in  the  erythrocytes  are 
absent. 

In  the  uncomplicated  case  of  measles  the 
Leucocytes,  number  of  leucocytes  is  either  normal  or  sub- 
normal. The  latter  change  is  very  common,  the 
decrease  of  leucocytes  being  most  marked  at  the  height  of  the  fever 
during  the  stage  of  eruption,  and  their  number  again  reaching  nor- 
mal coincidentally  with  the  fading  of  the  eruption  and  the  begin- 
ning of  desquamation.  The  count  may  fall  to  3000  or  4000  per 
c.mm.  during  the  period  of  maximum  temperature.  Combe9 
believes  that  leucopenia  is  constant  in  all  uncomplicated  cases, 
and  that  the  diminution  in  the  number  of  cells  amounts  to  at 

1  Loc.  cit.  2  Lancet,  1898,  vol.  i,  p.  221. 

Phila.  Med.  Jour.,  1899,  vol.  iv,  p.  491.  4  Loc.  cit. 

5  Amer.  Jour.  Med.  Sci.,  1903,  vol.  cxxv,  p.  105. 
8  Amer.  Year-book  of  Med.  and  Surg.,  1900,  p.  317. 

7  N.  Y.  Med.  Jour.,  1904,  vol.  lxxx,  p.  419. 

8  Centralbl.  f.  Bakt.  u.  Parasit,  1897,  vol.  xxi,  p.  286. 

9  Arch,  de  med.  des  Enf.,  1899,  vol.  ii,  p.  345. 


486 


GENERAL  HEMATOLOGY. 


least  one-half  the  normal  number;  he  finds  that  the  decrease  begins 
during  the  last  two  days  of  the  invasion  period,  and  persists 
through  the  stage  of  exanthem.  The  first  two  days  of  the  invasion 
period,  however,  are  characterized  by  a  moderate  leucocytosis, 
chiefly  involving,  according  to  Renaud,1  the  polynuclear  neu- 
trophiles.  This  author,  as  well  as  Combe,  also  found  a  striking 
degree  of  relative  lymphocytosis,  first  developing  during  the  early 
days  of  the  eruption.  All  cases,  however,  do  not  show  this  in- 
crease in  mononuclear  forms,  for  in  some  the  relative  percentages 
of  the  different  varieties  of  leucocytes  remain  as  in  health.  Cases 
with  decided  adenitis  and  those  with  persistent  diarrhea  most 
frequently  show  this  lymphocyte  increase.  The  eosinophiles  are 
usually  either  diminished  or  else  entirely  absent  during  the  feb- 
rile period  of  the  disease;  occasionally  they  reach  a  high  normal 
standard,  but  are  not  increased,  as  in  scarlet  fever.  Reckzeh2 
found  that,  as  a  rule,  the  eosinophiles  do  not  reach  their  normal 
value  until  the  end  of  the  second  week  after  invasion. 

Should  leucocytosis  develop,  it  should  be  attributed  to  some 
acute  inflammatory  complication,  such  as  bronchopneumonia, 
croupous  pneumonia,  or  severe  bronchitis. 

In  cases  with  anomalous  symptoms  the  exist- 
Diagnosis.  ence  of  scarlet  fever  may  often  be  excluded  by 
the  absence  of  leucocytosis.  Absence  of  increase 
in  fibrin  and  eosinophiles  is  also  suggestive  in  ruling  out  this 
infection.  If  the  diagnosis  lies  between  measles  and  syphilitic 
roseola,  the  absence  of  leucocytosis  points  to  the  former.  The 
initial  stage  of  variola  has  been  mistaken  for  measles,  but  the 
blood  examination  is  of  no  aid  in  differentiating  these  two  condi- 
tions, as  leucocytosis  is  not  found  in  small-pox  at  this  stage  of 
its  development.  Rotheln  does  not  give  rise  to  blood  changes 
distinguishable  from  those  of  true  measles.  This  was  true  of  nine 
cases  examined  by  Plantenga.3  Tchistovitch4  found,  in  four  cases, 
either  normal  blood  or  a  very  slight  neutrophile  increase. 

XLVIII.  MENINGITIS. 
The  condition  of  the  hemoglobin  and  erythro- 
Hemoglobin  cytes  has  not  been  extensively  studied  in  this 
and         disease,  but  so  far  as  the  data  at  present  avail- 
Erythrocytes.  able  show,  the  only  notable  change  to  be  observed 
consists  of  a  moderate  oligochromemia.  This 

1  Arch,  de  med.  des  Enf.,  1901,  vol.  iv,  p.  22. 
2Zeitschr.  f.  klin.  Med.,  1902,  vol.  xlv,  p.  107. 

3  Arch,  de  med.  des  Enf.,  1903,  vol.  vi,  p.  129. 

4  Russkiy  Vrach,  1904;  abst.,  Jour.  Amer.  Med.  Assoc.,  1904,  vol.  xlii,  p.  809. 


MKNINC.ITIS. 


487 


change,  however,  is  inconstant,  for,  as  a  rule,  both  the  number  of 
corpuscles  and  their  hemoglobin  value  arc  normal,  or,  perhaps, 
somewhat  above  normal. 

These  statements,  as  well  as  those  relating  to  the  leucocytes, 
apply  to  the  various  non-tuberculous  inflammations  of  the  cerebral 
and  spinal  pia-arachnoid  and  dura  mater,  acute  leptomeningitis 
and  pachymeningitis,  and  epidemic  cerebrospinal  meningitis. 
The  blood  changes  associated  with  tuberculous  meningitis  are 
described  elsewhere.    (See  pp.  546  and  549.) 

Well-defined  leucocytosis  is  found  in  the  great 
Leucocytes,  majority  of  instances,  the  counts  usually  ranging 
in  excess  of  20,000  to  the  c.mm.,  and  tending  to 
attain  highest  figures  in  purulent  meningitides. 

Forty-seven  cases  of  various  non-tuberculous  meningeal  in- 
flammations have  been  observed  by  Williams  and  by  Cabot,1  in 
all  but  two  of  which  the  leucocytes  at  the  first  examinations 
numbered  more  than  10,000  to  the  c.mm.,  and  in  the  individual 
case  as  high  as  40,000  and  50,000.  The  two  instances  in  which 
the  first  counts  failed  to  show  leucocytosis  were  cases  of  epidemic 
cerebrospinal  meningitis,  36  of  which  were  included  in  the  entire 
series.  In  37  cases  of  cerebrospinal  fever  Koplik2  found  leucocy- 
tosis a  constant  sign,  the  counts  ranging  from  12,000  to  55,000,  and 
exceeding  25,000  in  55  per  cent,  of  the  cases.  The  highest  leucocy- 
toses  were  found  in  fatal  cases,  in  which  lumbar  puncture  showed 
a  thick,  turbid,  pus-like  fluid. 

The  myth,  still  entertained  to  some  extent,  that  tuberculous 
and  non-tuberculous  meningitis  differ  in  that  the  former  does  not 
cause  leucocytosis,  should  have  been  dispelled  long  ago.  Thus, 
while  Turk3  found  this  sign  in  32  out  of  35  (or  91.4  per  cent.) 
counts  in  non-tuberculous  cases,  he  also  noted  it  in  4  out  of  8 
counts  in  the  tuberculous  form,  the  maximum  estimate  in  the 
latter  being  20,800  cells  per  c.mm.  Rieder4  has  reported  a  count 
of  14,400  in  one  case  of  tuberculous  meningitis,  and  in  another, 
7800  and  5900  cells;  leucocytosis  was  constant  in  this  author's 
10  counts  in  non-tuberculous  cases,  the  maximum  being  29,300. 
Examples  of  this  sort  could  be  still  further  multiplied  to  demon- 
strate that  leucocytosis  occurs  with  great  frequency  in  tuberculous 
meningitis. 

The  most  common  differential  change  consists  in  an  absolute 
and  relative  increase  in  the  polynuclear  neutrophiles,  this  alteration 
tending  to  become  most  striking  when  the  total  leucocyte  count 
is  excessively  high.    In  cases  with  a  normal  count,  or  with  only 

1  Loc.  cit.  2  Med.  News,  1904,  vol.  lxxxiv,  p.  1065. 

3  Loc.  cit.  4  Loc.  cit. 


488 


GENERAL  HEMATOLOGY. 


a  moderate  increase,  Turk  observed  a  relatively  high  percentage 
of  large  lymphocytes  and  transitional  forms,  and  he  has  further 
called  attention  to  the  fact  that  the  eosinophiles  are  either  absent 
or  decreased  to  a  small  fraction  of  one  per  cent,  in  practically 
every  count,  irrespective  of  the  presence  or  absence  of  an  increase 
in  the  total  number  of  leucocytes. 

Between  tuberculous  and  non-tuberculous  men- 

Diagnosis.    ingitis  an  absence  of  leucocytosis  strongly  sug- 
gests the  former,  although  the  presence  of  a 
leucocytosis  does  not  of  necessity  exclude  it. 

Epidemic  cerebrospinal  meningitis  sometimes  resembles  such 
infections  as  enteric  fever,  typhus  fever,  pneumonia,  and  malignant 
forms  of  variola.  In  attempting  these  diagnoses,  the  presence  of 
a  leucocytosis  almost  invariably  excludes  typhoid,  but  the  be- 
havior of  the  leucocytes  is  of  no  avail  as  a  means  of  differentiating 
pneumonia.  In  variola  the  early  development  of  a  large-celled 
mononucleosis,  often  with  myelemia,  proves  a  helpful  sign.  Most 
cases  of  typhus  show  a  normal  or  subnormal  number  of  leucocytes, 
but  some  with  moderate  leucocytosis  have  been  reported. 

Acute  meningitis  cannot  be  distinguished  by  the  blood  examina- 
tion from  cerebral  hemorrhage  and  abscess,  since  in  all  these  condi- 
tions high  counts  are  the  rule.  Cabot 1  believes  that  hysteria,  lead 
encephalopathy,  diabetic  coma,  sunstroke,  and  narcotic  or  alcoholic 
intoxication  can  be  excluded  by  the  presence  of  a  leucocytosis, 
and  that,  should  the  diagnosis  lie  between  meningitis,  on  the  one 
hand,  and  uremia  and  post- epileptic  coma,  on  the  other,  an  absence 
of  leucocytosis  is  sufficient  to  exclude  meningitis,  although,  its 
presence  is  of  no  diagnostic  value.  It  is  possible  that  bacterio- 
logical examination  of  the  blood  may  furnish  definite  information, 
for  Gwyn 2  has  succeeded  in  repeatedly  cultivating  the  Diplococcus 
meningitidis  intracellulars  from  the  blood  of  a  case  of  epidemic 
cerebrospinal  fever.  Several  investigators  have  found  pneumo- 
cocci  in  the  blood  in  cases  of  acute  meningitis. 


XLIX.  MYXEDEMA. 

Anemia,  involving  chiefly  the  hemoglobin,  is  a  finding  in  per- 
haps four-fifths  of  all  cases,  judging  from  Murray's 3  and  Bram- 
welPs4  records  of  56  patients.  More  rarely,  high  grade  anemia 
is  found  in  this  condition,  as  in  a  case  examined  by  Le  Breton,5  in 

1  Loc.  cit.  2  Johns  Hopkins  Hosp.  Bull.,  1899,  vol.  x,  p.  112. 

3  "Twentieth  Century  Practice  of  Medicine,"  New  York,  1895,  vol.  iv,  p.  710. 

4  "Anemia,"  London,  1899,  p.  309. 

5  Bull.  soc.  med.  des  hop.  de  Paris,  1895,  vol.  xii,  p.  22. 


NEPHRITIS. 


489 


which  the  loss  of  hemoglobin  amounted  to  45,  and  the  loss  of 
erythrocytes  to  66,  per  cent,  of  the  normal  standard,  with  a  color 
index  of  1.91.  This  author,  as  well  as  Kraepelin,1  in  several 
instances  has  observed  a  general  increase  in  the  diameter  of  the 
erythrocytes  and  the  presence  of  erythroblasts,  but  such  changes 
are  not  ordinarily  encountered. 

The  leucocytes  are  moderately  increased  in  a  small  proportion 
of  patients,  but  never  reach  notably  high  figures;  in  fully  three- 
fourths  of  cases  their  number  does  not  exceed  the  maximum 
normal  limit.  In  a  case  published  by  Putnam,2  a  small  number 
of  myelocytes  was  found,  but  no  other  differential  changes  of 
special  interest  have  been  reported. 

A  prompt  increase  in  the  hemoglobin  and  erythrocytes  follows 
the  administration  of  thyroid  extract  in  appropriate  doses,  but,  on 
the  other  hand,  excessive  thyroidization  rapidly  aggravates  the 
anemia,  according  to  B  ram  well. 3 


L.  NEPHRITIS. 

Important  contributing  factors  of  the  blood 
General     changes  in  this  condition  are  albuminuria,  hemor- 
Features.     rhage,  circulatory  disturbances,  and  the  character 
of  the  disease  with  which  the  renal  lesion  may  be 
associated.    The  fact  that  so  many  other  circumstances  are  ca- 
pable of  playing  active  etiological  roles  serves  to  explain  the  great 
dissimilarity  of  the  blood  pictures  in  different  nephritides  and  at 
different  stages  of  the  same  nephritis. 

Marked  albuminuria  produces  in  course  of  time  a  notable  drain 
upon  the  serum  proteids  and  a  less  conspicuous  deterioration  of 
the  corpuscles,  especially  affecting  their  volume.  By  this  agency, 
therefore,  the  specific  gravity  of  the  whole  blood  is  diminished,  in 
close  relationship  with  the  extent  of  the  drain  produced.  It  is 
still  a  disputed  question  whether  or  not  edema  may  also  be  held 
responsible  for  this  change.  The  investigations  by  Houston,4  of 
the  edema  of  anemia,  tend  to  prove  that  in  renal  disease  practically 
no  direct  relationship  exists  between  the  condition  of  the  blood 
and  the  extent  of  the  dropsy.  At  least  there  is  no  demonstrable 
relationship  in  cases  with  gradually  developing  edema,  owing 
doubtless  to  the  promptness  with  which  the  blood  mass  corrects 
any  tendency  to  dilution.  In  cases  with  hematuria  as  a  promi- 
nent symptom  the  familiar  picture  of  a  post-hemorrhagic  anemia 

J  Deutsch.  Arch.  f.  klin.  Med.,  1892,  vol.  xlix,  p.  587 

Amer.  Jour.  Med.  Sci.,  1893,  vol.  cvi,  p.  125. 
3  Loc-  ciL  4  Brit.  Med.  Jour.,  1902,  vol.  i,  p.  1464. 


49° 


GENERAL  HEMATOLOGY. 


may  be  encountered,  and  in  kidney  inflammations  which  ac- 
company an  acute  infectious  process  the  effects  of  the  latter  upon 
the  blood  are  to  be  remembered. 

The  amount  of  fibrin  may  be  found  to  be  increased,  especially 
in  contracted  kidney;  the  rate  of  coagulation  is,  so  far  as  has  been 
determined,  exceedingly  inconstant. 

Von  Jaksch,1  von  Limbeck,2  and  others  have  drawn  attention 
to  diminished  alkalinity  of  the  blood  as  a  sign  anticipating  and  ac- 
companying uremic  attacks. 

Bacteriological  examination  of  the  blood  proves  negative,  except 
in  the  terminal  stages  of  nephritis,  when  evidences  of  a  general 
circulatory  invasion  by  micro-organisms  may  sometimes  be  de- 
tected. Thus,  excluding  this  factor,  James  and  Turtle3  failed  to 
demonstrate  pathogenic  bacteria  in  the  blood  of  six  successive 
chronic  cases;  while,  on  the  other  hand,  White4  obtained  growths  of 
streptococci  in  three  consecutive  cases  of  chronic  parenchymatous 
nephritis,  on  the  second,  third,  and  fourth  days 'before  death, 
respectively,  these  positive  findings  being  attributed  to  terminal 
septicemia. 

In  acute  parenchymatous  nephritis  the  hemo- 
Hemoglobin  globin  and  erythrocyte  values  may  remain  per- 
and         fectly  normal,  or,  as  is  more  usual,  a  moderate 
Erythrocytes,  secondary  anemia  develops,  of  which  a  greatly 
disproportionate  oligochromemia  is  a  notable  fea- 
ture.   The  grade  of  the  anemia  is  highest  in  cases  with  marked 
albuminuria  and  hematuria,  but  only  exceptionally  is  a  loss  of 
more  than  2,000,000  per  c.  mm.  cells  noted.    Laache  5  estimates 
the  average  loss  in  hemoglobin  at  26  per  cent,  and  in  erythro- 
cytes at  19  per  cent.,  and  considers  that  the  decrease  is  much 
greater  in  acute  than  in  chronic  cases.    Hayem6  is  authority 
for  the  statement  that  striking  anemia  develops  only  in  cases 
with  hematuria. 

In  chronic  parenchymatous  nephritis  most  observers  state  that 
moderate  hemoglobin  and  erythrocyte  decreases  are  the  most 
notable  findings,  but  some  report  severe  anemia  the  grade  of 
which  is  likely  to  be  most  intense  in  cases  with  marked,  persistent 
albuminuria  and  with  associated  lesions  of  other  organs.  Sor- 
ensen7  found  that  the  count  of  erythrocytes  in  this  forrn  of  renal 
disease  averaged  4,700,000  to  the  c.mm.,  but  in  the  writer's  ex- 
perience a  much  more  pronounced  loss  has  been  observed — an 
average  hemoglobin  percentage  of  57.1  and  an  average  ery- 

1  Zeitschr.  f.  klin.  Med.,  1887,  vol.  xiii,  p.  350.  2  Loc.  cit.  3  Loc.  ciL 

4  Loc.  cit.  5  "Die  Anamie,"  Chnstiania,  1883. 

6  Loc.  cit.  7  Cited  by  Grawitz,  loc.  cit. 


NEPHRITIS. 


49 1 


throcyte  count  of  3,971,206  per  c.mm.,  in  a  series  of  15  cases.  A 
synopsis  of  the  examinations  in  these  cases  shows  the  following 
data:  Hemoglobin  percentage :  80-90  in  r;  70-80  in  2;  60-70  in  4; 
50-60  in  3 ;  40-50  in  2 ;  and  30-40  in  3.  Erythrocyte  counts :  above 
5,000,000  in  2;  4,000,000-5,000,000  in  4;  3,000,000-4,000,000  in  8;. 
2,000,000-3,000,000  in  1.  The  maximum  hemoglobin  estimate  in 
this  series  was  82,  and  the  minimum  30,  per  cent.;  the  maximum 
number  of  erythrocytes  per  c.mm.  was  5,520,000,  and  the  minimum 
2,270,000.    The  average  color  index  was  0.71. 

Polycythemia,  masking  the  real  condition  of  the  blood,  is  not 
at  all  uncommon;  it  may  arise  from  some  such  cause  as  cyanosis 
or  the  sudden  development  of  an  extensive  edema.  Every  clinician 
must  have  been  repeatedly  struck  by  the  evident  discrepancy 
between  the  blood  report  and  the  pinched,  waxy,  nephritic 
facies. 

In  chronic  interstitial  nephritis,  so  long  as  circulatory  disturb- 
ances do  not  exist,  the  condition  of  the  blood  remains  practically 
normal,  but  as  soon  as  the  compensatory  hypertrophy  of  the  left 
ventricle  becomes  inadequate,  the  blood  changes  identified  with 
uncompensated  valvular  heart  disease  develop,  and  various  de- 
grees of  apparent  anemia  and  polycythemia  become  evident  from 
time  to  time.  These  factors,  the  importance  of  which  is  insisted 
upon  by  Grawitz,1  no  doubt  serve  to  explain  most  of  the  blood 
changes  found  in  sclerotic  kidney,  but  it  seems  obvious  that 
neither  the  malnutrition  of  the  patient  nor  the  considerable  hem- 
orrhages from  which  he  often  suffers  should  be  disregarded  as 
possible  causes  of  blood  deterioration. 

All  the  structural  changes  affecting  the  erythrocytes  in  sec- 
ondary anemia  may  occur  in  association  with  any  of  the  preced- 
ing varieties  of  nephritis,  should  the  accompanying  anemia  be 
sufficiently  striking. 

In  acute  parenchymatous  nephritis  leucocytosis 
Leucocytes,  may  develop  in  the  early  stages  of  the  disease, 
and  persist  for  some  time  after  convalescence  is 
established.  Cabot,2  who  attributes  the  increase  to  the  effects 
of  hemorrhage  and  of  uremia,  found  it  present  in  about  80  per 
cent,  of  his  50  cases,  the  maximum  count  being  50,000  per  c.mm. 
Of  12  cases  in  which  these  two  factors  were  excluded  the  writer 
found  that  the  number  of  leucocytes  was  above  10,000  per  c.mm. 
in  9. 

In  the  15  cases  of  chronic  parenchymatous  nephritis  above 
mentioned,  the  number  of  leucocytes  averaged  8626  per  c.mm., 
the  maximum  being  16,000  and  the  minimum  4000.    Four  of 

1  Loc- ciL  2  Loc.  cit. 


492 


GENERAL  HEMATOLOGY. 


the  counts  were  in  excess  of  10,000;  9  from  5000-10,000;  and  2 
below  5000. 

Chronic  interstitial  nephritis  does  not  of  itself  influence  the 
number  of  leucocytes. 

Uremia  may  or  may  not  be  associated  with  leucocytosis ; 
the  change  is  to  be  noted  in  the  majority  of  nephritides  in  which 
this  complication  supervenes,  but  it  is  by  no  means  constant. 
Dopter  and  Gourand1  have  shown  that  in  rabbits  the  removal  of  one 
kidney  is  followed  by  a  transient,  doubtless  post-operative,  leuco- 
cytosis, but  that  after  a  double  nephrectomy  the  consequent 
uremic  intoxication  provokes  a  leucocytosis  which  persists  until  the 
animal's  death. 

In  all  the  above  forms  of  kidney  inflammation  the  leucocy- 
tosis, if  present,  is  of  the  polynuclear  neutrophile  type. 

The  blood  count  is  of  no  diagnostic  value  in 
Diagnosis,    nephritis,  nor  can  it  always  be  relied  upon  to  in- 
dicate accurately  the  richness  of  the  blood  in  cel- 
lular elements,  owing  to  the  frequent  prevalence  of  factors  which 
cause  dilution  and  inspissation. 


LI.  NERVOUS  AND  MENTAL  DISEASES. 

In  a  single  case  of  febrile  multiple  neuritis 
Neuritis,     Cabot2  found  a  moderate  degree  of  secondary 
Beri-beri,     anemia,  with  leucocytosis,  the  counts,  8  in  num- 
Neuralgia,   ber,  ranging  from.  16,000  to  28,700  per  c.mm., 
Brain  Tumor,  and  the  latter  figure  being  reached  during  the 
post-febrile  period  of  the  attack.    This  author 
also  noted  a  moderate  anemia  and  leucocytosis  in  4  of  6  cases 
of  alcoholic  neuritis,  but  found  the  number  of  leucocytes  normal 
in  25  cases  of  plumbic  neuritis. 

Beri-beri,  according  to  Spencer,3  is  usually  associated  with  a 
well-defined  secondary  anemia,  in  some  instances  characterized 
by  striking  qualitative  changes  affecting  the  size  and  shape  of  the 
erythrocytes.  The  leucocytes,  both  in  number  and  in  the  rela- 
tive percentages  of  their  different  varieties,  remain  normal,  ex- 
cept in  the  acute  stages  of  the  infection,  when  an  increase  in  the 
eosinophiles  may  develop.  Fajardo4  has  detected  a  spore-form- 
ing, pigment-producing  hematozoon,  and  Rost 5  a  diplobacillus, 
in  the  blood  of  beri-beri  patients,  each  of  which  organisms  has 

1  Sem.  med.,  1903,  vol.  xxiii,  p.  14. 

2  Loc.  cit.  3  Lancet,  1897,  vol.  i,  p.  32. 

4  Centralbl.  f.  Bakt.  u.  Parasit.,  1900,  vol.  xxvii,  p.  249. 

5  Lancet,  1901,  vol.  i,  p.  66. 


NERVOUS  AND  MENTAL  DISEASES. 


493 


been  regarded  by  their  respective  discoverer  as  the  specific  cause 
of  the  disease.  Other  investigators,  notably  Affleck,1  have  ob- 
tained negative  results  from  bacteriological  blood  examinations. 
In  the  blood  of  negroes  suffering  from  akatama,  a  form  of  peripheral 
neuritis  endemic  in  Central  Africa,  Wellman 2  has  found  the  para- 
sites of  both  tertian  malarial  fever  and  of  filariasis ;  he  concludes, 
however,  that  neither  of  these  parasites  has  any  etiological  bearing 
on  akatama,  for  they  are  frequently  harbored  by  natives  exempt 
from  this  disease. 

Neuralgia,  whatever  its  seat,  is  capable  of  exciting  neither 
anemia  nor  leucocytosis.  Excessive  polycythemia  (9,000,000  ery- 
throcytes per  c.mm.,  with  125  per  cent,  of  hemoglobin)  was  found 
by  F.  P.  Weber 3  in  a  case  of  erythromelalgia. 

The  blood  in  brain  tumor  usually  deviates  in  no  manner  from 
the  normal,  although  rarely  a  moderate  leucocytosis  has  been 
observed.  In  five  cases  the  writer  found  that  the  hemoglobin 
averaged  72.2  per  cent,  (ranging  from  70  to  79),  and  the  ery- 
throcyte count  3,800,000,  the  maximum  being  4,270,000  and  the 
minimum  2,860,000  per  c.mm.  None  of  the  cases  showed  leucocy- 
tosis, the  average  count  of  leucocytes  being  7320.  This  is  a 
distinct  contrast  to  cerebral  abscess  and  hemorrhage,  in  both  of  which 
conditions  leucocytosis  is  the  general  rule.  The  condition  of  the 
blood  in  meningitis  has  already  been  described.    (See  p.  486.) 

Neurasthenia,  hypochondriasis,  and  hysteria, 
Functional  while  they  do  not  primarily  serve  as  factors  of 
Neuroses,  blood  deterioration,  are  in  some  instances  associ- 
ated with  other  conditions  which  lead  to  moderate 
secondary  anemia,  usually  involving  chiefly  the  hemoglobin,  and 
but  rarely  causing  any  appreciable  diminution  in  the  number  of 
erythrocytes^  But,  as  a  rule,  functional  neurotics  have  normal 
blood  in  spite  of  their  anemic  appearance.  Luxemberg,4  in  a 
study  of  40  cases  of  hysteria  and  neurasthenia,  found  that  poly- 
cythemia was  common,  having  repeatedly  noted  erythrocyte 
counts  as  high  as  6,000,000,  and  even  in  one  instance  7,300,000, 
per  c.mm.;  he  attributes  this  to  vasomotor  changes,  possibly 
due  in  large  part  to  the  effect  of  the  examination  itself.  Reinert,5 
examining  74  cases  of  these  two  forms  of  neurosis,  found  a  moder- 
ate hemoglobin  diminution  in  many  cases  of  hysteria,  but  normal 
blood  in  neurasthenia.  In  sexual  neurasthenia,  however,  anemia 
is  not  at  all  uncommon,  in  the  writer's  experience.  MacPhail6 

1  Edinburgh  Med.  Jour.,  1900,  vol.  viii,  p.  33. 

2  Jour.  Trop.  Med.,  1903,  vol.  vi,  p.  267. 

3  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  1017. 

4  Centralbl.  f.  inn.  Med.,  1899,  vol.  xx,  p.  533. 

5  Munch.  med.-Wochenschr.,  1895,  vol.  xlii,  p.  305. 

6  Jour.  Mental  Sci.,  1884,  vol.  xxx,  pp.  378  and  488. 


494 


GENERAL  HEMATOLOGY. 


speaks  of  the  marked  anemia  usually  found  in  insane  masturbators, 
and  every  clinician  who  has  made  many  routine  blood  counts  must 
have  been  struck  with  the  fact  that  the  pallid,  pasty  face  of  the  con- 
firmed masturbator  but  seldom  falsely  reflects  the  state  of  the 
sufferer's  blood. 

The  functional  neuroses  are  not  accompanied  by  leucocytosis, 
but,  on  the  other  hand,  in  many  cases  a  decided  leucopenia  is 
present.  In  all  a  relatively  increased  proportion  of  lympho- 
cytes may  frequently  be  observed,  while  in  hysteria  the  num- 
ber of  eosinophiles  may  be  relatively  in  excess  of  the  normal 
standard. 

MacPhail,1  in  a  prize  essay  submitted  to  the 
General  Medico-Psychological  Association  of  Great 
Paresis,  Britain  in  1884,  concludes  that  these  mental  dis- 
Dementia,  eases  are  in  many  instances  closely  associated 
Melancholia,  with  a  more  or  less  decided  anemia,  although  in 
Mania.  no  sense  can  blood  deterioration  be  regarded  as  a 
factor  of  insanity.  In  general  paresis  this  ob- 
server found  subnormal  hemoglobin  values,  averaging  about  67  per 
cent.,  on  the  patient's  first  admission  to  the  hospital,  but  later,  as 
the  patient  profited  by  the  improved  hygienic  environment,  this 
value  rose,  only  again  to  fall  to  an  average  of  52  per  cent,  in  the 
terminal  stages  of  the  affection.  The  oligocythemia  steadily  in- 
creased as  the  disease  progressed,  and  occasionally  reached  in  the 
individual  case  a  minimum  count  of  between  3,000,000  and  4,000,- 
000  erythrocytes  per  c.mm.;  it  was  more  striking  during  the  active 
and  completely  paretic  stages  than  during  the  intervening  periods 
of  quiescence.  A  well-defined  leucocytosis  was  constant,  and 
many  of  the  counts  made  shortly  before  death  reached  high 
figures.  Diefendorf,2  in  n  paretics,  also  noted  a  progressive 
anemia,  generally  of  the  so-called  "chlorotic"  type,  together  with 
a  steady  gain  in  the  polynuclear  neutrophile  leucocytes,  which 
attained  its  acme  during  the  terminal  stage.  At  this  time  there 
developed  a  distinct  leucocytosis,  as  well  as  an  increase  in  the 
hemoglobin  and  erythrocyte  figures.  Paralytic  seizures  were 
accompanied  by  moderate  leucocytosis,  usually  not  exceeding  a 
count  of  20,000.  Capps,3  in  a  study  of  19  cases,  found  that  the 
hemoglobin  averaged  85  per  cent,  and  the  erythrocytes  4,789,900 
per  cmm. — figures  which  may  be  compared  with  Smyth's  average 
estimates4  in  40  cases:  hemoglobin,  68.7  per  cent.,  and  erythro- 
cytes, 4,700,000.  Capps  states  that  the  majority  of  cases  show 
a  moderate  leucocytosis,  averaging  an  increase  of  22  per  cent,  in 

1  Loc.  cit.  2  Amer.  Jour.  Med.  Sci.,  1903,  vol.  cxxvi,  p.  1047. 

3  Ibid.,  1896,  vol.  cxi,  p.  650.  4  Jour.  Mental  Sci.,  1890,  vol.  xxxvi,  p.  504. 


NERVOUS  AND  MENTAL  DISEASES. 


495 


excess  of  the  normal  standard,  but  that  in  the  incipient  stages  of  the 
disease  the  number  of  leucocytes  usually  is  not  increased.  An 
average  count  of  8800  was  noted  by  Somers 1  in  5  cases.  Relatively 
high  percentages  of  polynuclear  neutrophils,  with  a  diminution  in 
the  small  lymphocytes,  are  common  differential  changes,  while  the 
relative  numbers  of  large  lymphocytes  and  eosinophiles  may  be 
higher  than  normal.  The  eosinophiles  were  found,  by  Roncoroni,2 
to  be  regularly  increased  in  paretic  excitement — sometimes  as 
high  as  20  or  25  per  cent.  Kippel  and  Lefas,3  in  22  cases, 
invariably  found  from  1  to  4  per  cent,  of  basophiles ;  early  in  the 
disease  a  polynuclear  neutrophil  increase  was  the  rule,  but  in 
the  later  stages  it  declined  until  finally  lymphocytosis,  usually  but 
relative,  supervened. 

Convulsions  and  apoplectiform  attacks  tend  to  produce  blood 
concentration,  and  therefore  temporarily  increase  the  hemo- 
globin and  erythrocyte  values.  During  and  following  such 
seizures  an  abrupt  rise  in  the  leucocyte  curve,  characterized  by 
a  striking  absolute  and  relative  gain  in  the  large  lymphocytes, 
and,  rarely,  by  the  appearance  of  myelocytes,  was  observed  by 
Capps,  who  has  also  described  a  small  mononuclear  neutro- 
philic leucocyte,  resembling  a  dwarf  myelocyte,  as  peculiar  to 
the  condition  in  question.  (See  p.  222.)  Burrows4  believes  that 
the  leucocytosis  associated  with  convulsions,  not  only  in  general 
paralysis,  but  in  other  conditions,  bears  a  definite  relation  to 
the  severity  of  the  fit,  and  that  the  increase  is  in  part  the ,  result 
of  the  muscular  contractions  attending  the  convulsion,  and  in  part 
represents  an  actual  pathological  leucocytosis.  In  23  cases  of 
general  paresis  a  lowered  blood  alkalinity  was  constantly  found 
by  Pugh,5  the  diminution  being  most  notable  in  the  acuter  forms 
of  the  disease  and  in  connection  with  convulsive  seizures.  Acute 
delirium  from  any  cause  also  provokes  leucocytosis. 

In  dementia,  according  to  Smyth,6  both  the  hemoglobin  and  the 
erythrocytes  are  decidedly  lower  than  in  the  preceding  condition, 
his  averages  for  this  disease  being  53.7  per  cent,  of  hemoglobin 
and  a  count  of  4,070,000  erythrocytes  in  a  series  of  12  cases. 
In  10  cases  of  melancholia  he  found  that  the  hemoglobin  averaged 
69.7  per  cent,  and  the  erythrocytes  4,684,000,  while  Steel,7  in 
35  cases  of  this  disease,  estimated  the  average  hemoglobin  value 
at  75  per  cent,  and  the  average  erythrocyte  count  at  3,000,000. 

1  Bull.  N.  Y.  State  Hosp.,  1896. 

2  Arch.  d.  Psychiat.  Sc.,  1894,  vol.  xv,  p.  293. 

3  Sem.  med.,  1902,  vol.  xxii,  p.  393. 

4  Amer.  Jour.  Med.  Sci.,  1899,  vol.  cxvii,  p.  503. 

5  Jour.  Mental  Sci.,  1903,  vol.  xlix,  p.  71. 

6  Loc-  ciL  7  Amer.  Jour.  Insanity,  1892,  vol.  xlix,  p.  604. 


496 


GENERAL  HEMATOLOGY. 


In  acute  mania  anemia  of  the  so-called  "chlorotic"  type  usually 
may  be  observed;  this  blood  change  becomes  aggravated  by  each 
acute  maniacal  outbreak,  but  after  recovery  from  these  attacks 
the  deficiency  is  rapidly  restored.  In  acute  continuous  mania 
Bruce1  believes  that  the  number  of  leucocytes  stands  in  direct 
relation  to  the  improvement  of  the  patient,  convalescents  showing 
a  progressive  leucocytosis  with  a  high  percentage  of  polynuclear 
neutrophiles,  which  persists  after  recovery,  but  which  rapidly 
diminishes  should  a  relapse  occur.  This  investigator 2  also 
cultured  from  the  blood  a  diplobacillus,  indifferently  agglutinable 
by  the  serum  of  patients  suffering  from  mania,  and  non-patho- 
genic for  laboratory  animals.  Bruce  interprets  his  findings  as 
evidence  that  some  cases  of  mania,  at  least,  are  true  infections. 
Opposed  to  the  above  leucocyte  formula  of  acute  mania  are  the 
observations  of  Johnson  and  Goodall,3  who  found  the  count 
highest  during  the  acute  stages  and  lowest  during  states  of  remis- 
sion and  recovery.  These  investigators  have  also  shown  that  in 
60  per  cent,  of  all  cases  of  mania,  paresis,  and  other  forms  of 
insanity  the  patient's  blood  clumps  the  colon  bacillus.  This 
suggests  that  in  these  diseases  the  normal  inhibition  of  this  or- 
ganism's growth  in  the  gut  is  interfered  with,  and  in  consequence 
its  proliferation  is  excessive  enough  to  excite  toxemia.  Somers'4 
leucocyte  counts  in  19  dements  averaged  10,743,  in  19  melancholies 
7947,  and  in  19  maniacs  8315.  The  alkalinity  of  the  blood  re- 
mains normal,  except  in  patients  with  great  motor  restlessness,  in 
whom  subnormal  figures  are  the  rule.  The  following  table  of 
averages  by  Wherry  5  relates  to  the  blood  changes  in  95  cases  of 
dementia,  melancholia,  and  mania: 


Form  of  Insanity. 


Mania,  acute,  men  

Mania,  acute,  women  

Melancholia,  acute,  men  

Melancholia,  acute,  women.. 

Mania,  chronic,  men  

Mania,  chronic,  women  

Melancholia,  chronic,  men... 
Melancholia,  chronic,  women 

Dementia,  men  

Dementia,  women  


Hemoglobin. 


84  per  cent. 
68 

78  « 

77 

82 

71  " 
77  " 
77  " 
71 

73 


Erythrocytes. 


3,780,000 

7,800 

3;554,4oo 

7,600 

4,051,200 

6,400 

3>793>6o° 

7,400 

3,798,400 

7,100 

3,708,000 

8,200 

3,624,000 

6,700 

3,764,800 

7,200 

3>5i8,4oo 

7,600 

2,976,000 

9,200 

Leucocytes. 


1  Jour.  Mental  Sci.,  1903,  vol.  xlix,  p.  441. 

2  Ibid.,  1903,  vol.  xlix,  p.  219.  3  Lancet,  1903,  vol.  ii,  p.  47°- 

4  Loc  cn  5  Amer.  Med.,  1901,  vol.  ii,  p.  70. 


NERVOUS  AND  MENTAL  DISEASES. 


497 


In  family  periodic  paralysis  J.  K.  Mitchell 1  finds  that  the 
hemoglobin  and  corpuscular  figures  and  the  differential  leucocyte 
counts  do  not  deviate  from  normal.  High  blood  alkalinity  was 
detected,  both  during  the  paralytic  attacks  and  in  the  intervals 
between  them. 

In  epilepsy  a  moderate  anemia  appears  to  be 
Epilepsy.     the  general  rule.    Smyth's  studies2  of  50  cases 
Chorea.      show  an  average  of  62.8  per  cent,  of  hemoglobin, 
Tetany.      and  4,520,000  erythrocytes  per  c.mm.  Mac- 
Phail3  asserts  that  prolonged  attacks  of  excite- 
ment notably  increase  the  anemia,  but  that  the  habitual  admin- 
istration of  bromids  seems  in  no  manner  to  produce  deleterious 
effects  upon  the  blood.    Furthermore,  this  author  observed  that 
a  close  relationship  can  be  distinguished  between  the  patient's  gain 
in  weight,  the  decrease  in  the  anemia,  and  the  mental  improve- 
ment, and  that  in  patients  who  recovered,  the  regeneration  of  the 
blood  became  practically  complete.    Distinct  leucocytosis  seldom 
occurs  in  epilepsy,  except  as  the  result  of  a  convulsion.  Kuhl- 
mann,4  for  example,  found  the  leucocytes  in  excess  of  normal  but 
once  in  a  study  of  16  cases.    In  a  series  of  7  cases,  Pearce  and 
Boston5  found  well-marked  chloro- anemia  and  usually  a  moderate 
leucocyte  increase.    Differentially,  the  most  conspicuous  changes 
were  a  reduction  in  the  polynuclear  neutrophiles  and  the  inconstant 
presence  of  small  numbers  of  myelocytes. 

Pugh's  studies6  of  40  epileptics  tend  to  show  that  the  alkalinity  of 
the  blood  is  subnormal  during  the  period  between  epileptic  attacks, 
that  it  decidedly  falls  immediately  before  a  fit,  and  that  a  further 
fall  occurs  soon  after  a  fit  is  over.  Pugh  attributes  the  lowered 
alkalinity  partly  to  an  accumulation  of  acid  toxins  in  the  blood  and 
partly  to  an  output  of  sarcolactic  and  carbonic  acids  as  the  result 
of  the  violent  convulsive  attacks.  The  administration  of  strontium 
bromid  and  potassium  bicarbonate  for  a  time  restores  the  normal 
blood  alkalinity  and  apparently  diminishes  the  number  of  fits — but 
only  for  a  brief  period,  since  it  is  impossible  permanently  to  in- 
fluence the  reaction  of  the  blood  by  drug  giving.  Bra  and  Chausse 7 
describe  a  "  neurococcus "  in  the  blood  during  epileptic  fits,  and 
claim  to  have  cultured  the  alleged  germ  and  to  have  produced 
convulsions  in  animals  by  its  injection.  Bra's  claim  for  his 
neurococcus  as  the  cause  of  idiopathic  epilepsy  has  been  con- 


1  Brain,  1902,  vol.  xxv,  p.  109;  also  Trans.  Assoc.  Amer.  Phys.,  1899,  vol. 
xiv,  p.  345. 

2  Loc.  cit.  s  ioc  ciL 


5  Medicine,  1904,  vol.  x,  p.  123. 
Rev.  Neuroli.  and  Psychiat.,  1903,  vol.  i,  p.  689. 


32 


498 


GENERAL  HEMATOLOGY. 


tro verted  by  Tirelli  and  Brossa,1  who  obtained  uniformly  negative 
bacteriological  blood  findings  in  this  condition. 

In  chorea  slight  anemia,  usually  of  the  "chlorotic"  type,  occurs 
with  frequency,  but  not  with  constancy,  for  many  cases  habitually 
show  normal  hemoglobin  and  erythrocyte  values.  It  seems 
scarcely  necessary  to  remark  that  the  belief  once  entertained,  that 
blood  deterioration  was  a  causal  factor  of  this  disease,  is  obviously 
erroneous.  Burr,2  in  a' study  of  the  hemoglobin  and  erythrocytes 
in  36  cases,  concludes  that  a  moderate  diminution  in  both  of  these 
elements  is  the  general  finding,  and  that  a  high  grade  of  anemia 
occurs  only  as  the  result  of  some  complication.  The  oligocy- 
themia usually  does  not  exceed  a  loss  of  more  than  1,000,000 
cells  per  c.mm.  in  uncomplicated  cases.  The  leucocytes  are  not 
increased,  but  differential  counts  may  detect  a  relatively  large 
percentage  of  eosinophiles,  according  to  the  reports  of  Zappert 3 
and  others.   Tetany  is  not  of  itself  a  cause  of  blood  impoverishment. 


LII.  OBESITY. 

From  Kisch's  studies 4  it  is  evident  that  the  hemoglobin  values 
are  notably  high  in  most  corpulent  individuals,  and  in  some  ex- 
cessively increased.  In  79  of  100  cases  of  obesity  examined  by 
this  author  the  hemoglobin  percentage  exceeded  100,  while  in 
the  remaining  21  moderate  oligochromemia  was  found.  The 
maximum  reading  in  this  series  was  120  and  the  minimum  55 
per  cent.  Actual  anemia,  however,  is  not  incompatible  with  this 
class  of  patients,  as  demonstrated  by  Leichtenstern5  and  by 
Oertel.6  The  latter  also  maintains  that  in  some  instances  true 
plethora  exists,  and  furthermore  professes  to  recognize  two  dis- 
tinct forms  of  obesity,  an  anemic  and  a  plethoric.  Data  regarding 
the  leucocytes  in  this  condition  are  wanting. 


LIII.  OSTEOMALACIA. 

The  hemoglobin  and  erythrocytes  do  not  exhibit  any  marked 
deviations,  being  in  most  instances  normal,  or  but  moderately  di- 
minished. The  anemia,  when  present,  is  characterized  by  a 
hemoglobin  loss  relatively  exceeding  that  of  the  corpuscles. 

1  Rif.  Med.,  1903,  vol.  xix,  p.  934. 

2  Univ.  Med.  Mag.,  1896,  vol.  ix,  p.  188. 

3  Zeitschr.  f.  klin.  Med.,  1893,  vol.  xxiii,  p.  227.  4  Ibid.,  1887,  vol.  xii,  p.  357. 
6  "Untersuch.  u.  d.  Hg-Gehalt  d.  Blutes,"  Leipsic,  1878. 

6  "Allgem.  Ther.  d.  Kreislaufsstor.,"  Leipsic,  1884;  also  Deutsch.  Arch.  f. 
klin.  Med.,  1892,  vol.  i,  p.  293. 


PANCREATITIS. 


499 


The  leucocytes  also  remain  approximately  normal  in  number, 
slight  fluctuations  above  and  below  this  standard  being  the  only 
numerical  change  thus  far  noted.  Relative  lymphocytosis  has 
been  found  by  Ritchie  1  and  by  Tschistowitch,2  while  Neusser 3 
and  others  have  observed  in  many  cases  a  moderate  increase  in 
the  eosinophils,  and  the  presence  of  small  numbers  of  myelo- 
cytes. None  of  these  differential  changes,  however,  is  to  be 
considered  constant  in  this  condition.  According  to  von  Lim- 
beck,4 the  alkalinity  of  the  blood  remains  practically  unaltered, 
although  von  Jaksch5  formerly  maintained  that  it  was  considerably 
diminished. 

LIV.  PANCREATITIS. 

In  interpreting  the  blood  picture  of  pancreatitis  due  attention 
should  be  paid  to  the  influence  of  possible  attendant  lesions, 
especially  those  such  as  cholangitis,  peritonitis,  icterus,  and  dia- 
betes. Acute  hemorrhagic  pancreatitis  is  so  frequently  part  and 
parcel  of  abscess,  gangrene,  and  sepsis  that  more  or  less  anemia  is 
to  be  expected.  As  a  rule,  the  hemoglobin  and  erythrocyte  losses 
are  moderate,  although  exceptionally  the  values  approximate  but 

25  or  30  per  cent,  of  normal.  The  dual  factors,  hemorrhage  and 
acute  inflammation,  not  to  mention  infection  and  necrosis,  are 
ideal  theoretical  reasons  for  a  leucocytosis,  and,  practically,  it  is 
found  that  these  factors  are  active.  Seven  examinations  in  four 
cases  of  acute  pancreatic  inflammation  in  the  German  Hospital 
gave  these  averages:  hemoglobin,  57.1  per  cent.,  ranging  between 

26  and  88;  erythrocytes,  3,205,714  per  c.mm.,  ranging  between 
1,550,000  and  4,460,000;  and  leucocytes,  19,292  per  c.mm., 
ranging  between  11,600  and  32,000.  The  histological  changes  are 
those  attending  secondary  anemia  and  a  polynuclear  neutrophile 
leucocytosis. 

Chronic  pancreatitis,  being  a  slow  sclerosis,  has  little  or  no 
effect  upon  the  blood.  Nine  estimates  in  three  German  Hospital 
cases  averaged  80.2  per  cent,  of  hemoglobin,  with  extremes  of  54 
and  99;  4,700,000  erythrocytes  per  c.mm.,  or  a  range  of  from  3,600,- 
000  to  5,900,000;  and  7188  leucocytes  per  c.mm.,  ranging  be- 
tween 4000  and  11,300.  In  non- inflammatory  pancreatic  cyst  a. 
similar  blood  picture  is  found,  while  if  the  cyst  is  actively 
inflamed,  a  varying  degree  of  leucocytosis  generally  develops.. 
In  pancreatic  lithiasis  the  blood  changes  may  be  those  of  acute 

1  Edinburgh  Med.  Jour.,  1896,  vol.  xlii,  p.  208. 

2  Berlin,  klin.  Wochenschr.,  1893,  vol.  xxx,  p.  919. 

3  Wien.  klin.  Wochenschr.,  1892,  vol.  v,  p.  41. 

4  Loc.  cit.  5  Zeitschr.  f.  klin.  Med.,  1887,  vol.  xiii,  p.  350. 


5°° 


GENERAL  HEMATOLOGY. 


or  chronic  pancreatitis  or  of  malignant  disease,  depending  upon  the 
effects  of  the  stones.  The  blood  in  pancreatic  malignant  neoplasm 
has  already  been  considered.    (See  "Malignant  Disease,"  p.  472.) 

Aside  from  the  facts  that  anemia  and  leucocytosis  attend  acute 
rather  than  latent  inflammations  of  the  pancreas,  and  that  a 
leucocytosis  argues  the  malignancy  of  a  tumor  of  this  organ,  the 
blood  examination  is  of  no  definite  value  in  recognizing  pancreatic 
lesions. 

LV.  PERICARDIAL  EFFUSION. 

The  hemoglobin  and  erythrocytes  remain  normal,  or,  if  anemia 
is  found,  it  may  be  referred  to  other  coexisting  conditions. 

Leucocytosis  of  the  polynuclear  neutrophile  type  is  practically 
a  constant  change  in  the  non-tuberculous  forms,  but  in  tuber- 
culous pericarditis  the  leucocytes  apparently  do  not  increase. 
From  a  diagnostic  viewpoint  the  presence  of  a  leucocytosis  is  of 
real  value  in  excluding  the  latter  condition,  as  well  as  cardiac 
dilatation;  this  sign  is  also  strong  evidence  against  the  existence 
of  a  serous  pleural  effusion,  which,  if  left-sided,  may  simulate 
pericarditis. 

LVI.  PERITONITIS. 

Anemia  is  frequently  found,  the  degree  of 
Hemoglobin  which  largely  depends  upon  the  character  and 
and  the  chronicity  of  the  inflammation.  In  general 
Erythrocytes,  purulent  peritonitis,  especially  in  cases  of  com- 
paratively long  standing,  the  hemoglobin  and 
erythrocyte  diminution  may  be  excessive— to  between  20  and  30 
per  cent  for  the  former,  and  to  between  2,000,000  and  3,000,000 
per  c.mm.  for  the  latter.  With  such  an  anemia  as  this  the  ery- 
throcyte loss  is  commonly  very  disproportionate  to  that  of  the 
hemoglobin,  so  that  high  color  indices  rule;  for  example,  in  three 
of  the  cases  summarized  below,  the  indices  were  1.12,  1.01,  and 
1. 00  respectively.  The  several  qualitative  changes  accompanying 
any  severe  secondary  anemia  are  also  commonly  to  be  observed. 
Serous  peritonitis  has  but  little  effect  in  provoking  a  cellular 
decrease,  although  it  usually  causes  a  slight  but  definite  oli- 
gochromemia,  so  that  in  such  cases  the  color  indices  are  moderately 
subnormal.  On  the  average,  it  may  be  stated  that  peritonitis 
involves  a  loss  of  about  30  per  cent,  of  hemoglobin  and  of  25  per 
cent,  of  erythrocytes. 

The  following  summary  of  54  cases,  none  of  which  was  ap- 
pendicular, shows  the  grade  of  anemia  prevailing  in  this  disease: 


PERITONITIS. 


Number  ok 
Cases. 


Hemoglobin 
Percentage. 

From  90-IOO. 

"    80-  go. 

"    70-  80. 

"    60-  70. 

"    50-  60. 

"    40-  SO. 

"    3°"  40- 

"    20-  30. 
Average,     68.4  per  cent. 
Maximum,  93.0  " 
Minimum,  20.0  " 


15 
10 

9 
6 

7 

3 

2 


Erythrocytes  Number  of 

per  c.mm.  Cases. 

Above  5,000,000   

From  4,000,000-5,000,000.. 

"  3,000,000-4,000,000.. 

"  2,000,000-3,000,000.. 


1 ,000,000-2,000,000 . 


Average,     3,756,035  per  c.mm. 
Maximum,  5,670,000   "  " 
Minimum,  1,290,000   "  " 


5 
23 
14 
7 
5 


Provided  that  the  patient's  resisting  powers 
Leucocytes,  react  normally,  septic  peritonitis  constantly  causes 
a  typical  leucocytosis  of  the  polynuclear  neutro- 
phil variety.  Generally  speaking,  80  per  cent,  of  cases  show  a 
leucocyte  count  of  10,000  or  higher.  It  cannot  be  stated  with 
certainty  that  the  increase  is  greater  in  purulent  than  in  serous 
inflammations,  for  any  variety  of  peritonitis,  except  the  tubercu- 
lous, may  provoke  a  striking  leucocytosis.  As  already  remarked 
in  the  discussion  of  appendicitis,  extension  of  the  process  is  heralded 
by  an  abrupt  rise  in  the  leucocyte  curve.  As  in  other  infections, 
leucocytosis  may  be  absent,  or  leucopenia  may  exist,  in  cases  of  a 
profound,  crippling  character.  The  number  of  leucocytes  in  the 
preceding  54  cases  ranged  as  follows : 

Leucocytes  Number  of 

per  c.mm.  Cases. 

Above  45,000   I 

From  35,000-45,000   2 

"     25,000-35,000   2 

"     20,000-25,000   5 

"      15,000-20,000  12 

"      10,000-15,000  19 

5,000-10,000  12 

Below    5,000   1 

Average,     15,526  per  c.mm. 

Maximum,  46,000   "  " 

Minimum,    4,400   "  " 

The  presence  of  leucocytosis  is  sufficient  evi- 
Diagnosis.    dence  for  the  exclusion  of  tuberculous  peritonitis, 
so-called  hysterical  peritonitis,  and  rheumatism  of 
the  abdominal  muscles.    This  sign,  however,  cannot  safely  be 


5°2 


GENERAL  HEMATOLOGY. 


employed  to  differentiate  between  peritonitis  and  acute  enteritis, 
certain  forms  of  intestinal  obstruction,  and  rupture  of  a  tubal 
pregnancy  or  of  an  abdominal  aneurism,  all  of  which  may  cause 
more  or  less  leucocyte  increase.    (See  "  Appendicitis,"  p.  370.) 

Cabot1  regards  the  association  of  marked  leucocytosis  with 
hyperinosis  as  strongly  in  favor  of  a  peritoneal  inflammation 
rather  than  of  such  conditions  as  non-malignant  bowel  obstruction, 
malignant  disease,  hysteria,  and  phantom  tumors. 


LVII.  PERTUSSIS. 

Iodophilia  was  detected  by  Crisafi2  in  16  of  20  cases  examined, 
but  no  relationship  could  be  traced  between  this  sign  and  the 
presence  of  glycosuria,  which  developed  in  4  of  the  patients.  In 
so  far  as  can  be  learned  from  the  scanty  literature  at  present 
available,  the  hemoglobin  and  erythrocyte  values  remain  nor- 
mal in  this  disease.  Lymphocytosis,  generally  relative,  but 
sometimes  absolute,  is  a  characteristic  finding  in  whooping- 
cough.  As  a  consequence  of  this  change  there  is  a  coincident 
diminution  in  the  polynuclear  neutrophiles  and  eosinophiles. 
Frohlich  and  Meunier,3  who  originally  determined  this  fact,  found 
in  30  cases  an  average  of  27,800  leucocytes  per  c.mm.,  the  in- 
dividual counts  ranging  from  a  minimum  of  15,500  to  a  maximum 
of  51,150.  De  Amicis  and  Pacchioni4  have  corroborated  this 
observation,  although  they  consider  that  the  increase  is  some- 
what less,  having  found  an  average  count  of  17,943  for  their  cases. 
Wanstall,5  in  15  cases,  and  Stengel  and  White,6  in  4,  obtained 
even  lower  total  leucocyte  values  (no  increase  being  noted  in 
many  instances),  but  found  a  lymphocyte  increase  the  rule.  The 
lymphocytosis  develops  during  the  early  stages  of  the  disease, 
before  the  cough  begins,  and  usually  persists  for  some  time  after, 
convalescence  is  established.  As  a  general  rule,  it  may  be  stated 
that  the  younger  the  child,  the  more  notable  the  increase.  Such 
complications  as  bronchitis,  catarrhal  pneumonia,  and  otitis  do 
not  appear  appreciably  to  exaggerate  it.  According  to  Ehrlich,7 
it  is  to  be  attributed  to  the  stimulation  and  swelling  of  the  tracheo- 
bronchial lymphatic  glands. 

The  fact  that  a  marked  lymphocyte  increase  occurs  in  the  early 
catarrhal  stages  of  the  disease,  antedating  the  development  of  the 

1  Loc.  cit.  2  Brit.  Med.  Jour.  Epit.,  1904,  vol.  i,  p.  49. 

3  Compt.  rend.  Soc.  biol.,  Paris,  1898,  vol.  v,  p.  103. 

4  Clinica  Medica,  1899,  vol.  iv,  p.  103. 
6  Amer.  Med.,  1903,  vol.  v,  p.  62. 

•6  Arch.  Pediat,  1901,  vol.  xviii,  pp.  241  and  321.  7  Loc.  cit. 


PLEURISY. 


typical  cough,  is  of  diagnostic  value,  as  is  also  the  presence  of 
iodophilia. 

LVIII.  PLEURISY. 
Serous  Pleurisy. 

In  acute  cases  it  is  customary  to  find  normal 
Hemoglobin  hemoglobin  and  erythrocyte  values,  or,  at  the 
and         most,  simply  a  moderate  oligochromemia ;  in 
Erythrocytes,  those  of  longer  standing,  with  decided  debility  of 
the  patient,  anemia,  sometimes  of  a  considerable 
degree,  is  not  an  uncommon  finding.    Thus,  in  an  instance  of  this 
sort  the  writer  found  but  38  per  cent,  of  hemoglobin  and  3,300,- 
000  erythrocytes  per  c.mm.,  together  with  the  corpuscular  de- 
generative changes  to  be  expected  in  an  anemia  of  this  intensity. 
It  is  to  be  remembered  that  a  rapidly  developing  pleural  effusion 
may  so  concentrate  the  blood  as  to  cause  a  temporary  polycy- 
themia, disguising  the  actual  quantitative  changes. 

Absence  of  leucocytosis  is  the  general  rule, 
Leucocytes,  probably  for  the  reason  that  almost  all  serous 
pleurisies  are  of  tuberculous  origin.  Exception- 
ally a  moderate,  intermittent  increase  is  found,  chiefly  affecting 
the  polynuclear  neutrophiles,  and  due  possibly  to  the  influence  of 
some  intercurrent  process,  such  as  a  secondary  pneumococcus  in- 
fection. A  notable  increase  in  the  eosinophiles  may  often  be  found 
in  hemorrhagic  pleural  effusions.  In  children  a  leucocytosis 
sometimes  occurs,  apparently  independent  of  secondary  infections. 
It  is  quite  evident  that  the  behavior  of  the  leucocytes  cannot  be 
used  as  a  means  of  differentiating  tuberculous  from  non-tubercu- 
lous effusions. 

Morse,1  in  a  study  of  224  examinations  made  in  20  cases, 
comes  to  the  conclusion  that  there  is  no  definite  relation  between 
the  leucocyte  count  and  the  duration  of  the  disease,  the  degree 
of  pyrexia,  the  amount  of  the  effusion,  and  its  increase  and  dim- 
inution. Neither  could  he  determine  that  the  contamination  of 
the  fluid  by  blood  and  by  microscopical  pus  produced  the  slightest 
effect  upon  the  number  of  cells.  In  Morse's  counts  the  number 
of  leucocytes  exceeded  10,000  to  the  c.mm.  in  5.8  per  cent.,  while 
in  Cabot's  99  cases2  this  figure  was  exceeded  in  14. 1  per  cent., 
the  average  count  for  the  latter  being  6130. 

1  Amer.  Jour.  Med.  Sci.,  1900,  vol.  cxx,  p.  658.  2  hoc.  cit. 


5°4 


GENERAL  HEMATOLOGY. 


Purulent  Pleurisy. 

The  changes  in  the  hemoglobin  and  erythro- 
Hemoglobin  cytes  do  not  differ  conspicuously  from  those  pre- 
and         vailing  in  primary  serous  pleurisy,  although  evi- 
Erythrocytes.  dences  of  a  decided  anemia  are  to  be  observed 
somewhat  more  frequently. 
In  8  of  the  writer's  10  cases  of  empyema  the  hemoglobin  loss 
exceeded  50  per  cent,  of  the  normal,  38  per  cent,  being  the  min- 
imum, 73  per  cent,  the  maximum,  and  46  per  cent,  the  average, 
estimate.    The  erythrocytes  were  below  2,000,000  to  the  c.mm. 
in  2  instances,  averaging  3,500,000,  with  1,540,000  as  the  minimum 
and  4,600,000  as  the  maximum,  counts. 

Leucocytosis,  ordinarily  of  a  high  grade,  ac- 
Leucocytes.  companies  the  great  majority  of  cases,  the  increase 
involving  mainly  the  polynuclear  neutrophile  cells 
at  the  expense  of  the  lymphocytes.  It  is  more  usual  to  find  the 
count  above  than  below  20,000  to  the  c.mm.,  and  in  an  exceptional 
instance  it  may  even  exceed  50,000.  Aspiration  of  the  pus  is 
followed  by  a  decline,  and  its  reaccumulation  by  a  rise,  in  the 
leucocyte  curve.  The  extent  of  the  primary  purulent  accumula- 
tion cannot  be  gaged  with  any  accuracy  by  the  degree  of  the 
leucocyte  increase. 

The  following  counts  in  a  case  of  empyema  examined  at  the 
German  Hospital  will  serve  to  illustrate  the  high  leucocytosis 
sometimes  seen  in  this  condition: 


Date. 

Hemoglobin 

Erythrocytes 

Leucocytes 

Percentage. 

PER  C.MM. 

PER  C.MM. 

Jan.  16,  1900  . . 

84 

4,460,000 

23,200 

"    17,  1900  . . 

88 
82 

5,380,000 

42,400 

"    18,  1900  . . 

4,320,000 

45,000 

"    19,  1900  . . 

82 

4,430,000 

40,800 

"    20,  1900  . . 

83 

4,383,000 

23,320 

"    21,  1900  . . 

82 

4,410,000 

44,300 

"    22,  1900  . . 

81 

4,330,000 

40,600 

"    23,  1900  . . 

7i 

3,985,000 

37,3°° 

"    24,  1900  . . 

67 

4,360,000 

53>5°° 

"    26,  1900  . . 

83 

4,240,000 

47,100 

"    27,  1900  . . 

7i 

3,480,000 

48,100 

In  to  other  cases  above  noted  a  leucocyte  increase  was  in- 


PNEUMONIA. 


505 


variably  found,  the  counts  averaging  17,180  and  ranging  from 
11,200  to  31,800  per  c.mm. 

The  presence  of  a  well-developed  leucocytosis 
Diagnosis,  points  to  pneumonia  or  empyema,  rather  than  to 
simple  serous  pleurisy,  but  it  does  not  differentiate 
between  these  first  two  conditions.  On  the  other  hand,  an  ab- 
sence of  leucocytosis  does  not  surely  exclude  pneumonia  and 
empyema,  although  it  is  extremely  suggestive  that  neither  exists. 
Malignant  neoplasms  of  the  lungs  and  pleura  also  cause  a  decided 
leucocyte  increase,  as  does  actinomycosis. 


LIX.  PNEUMONIA. 

In  the  case  of  average  severity,  coagulation  is 
General  exceedingly  rapid,  and  the  amount  of  fibrin 
Features,  greatly  increased,  the  network  being  dense, 
coarse,  and  formed  with  great  rapidity.  The 
hyperinosis  tends  to  persist  for  some  time  after  the  disappearance 
of  the  pyrexia  and  the  signs  of  lung  involvement.  In  severe  in- 
fections, occurring  in  individuals  of  good  resisting  powers,  the 
change  is  especially  striking,  but  in  fatal  cases,  overwhelmed  by  the 
disease,  a  fibrin  increase  is  not  observed.  High  temperature  and 
extensive  infiltration  of  the  lungs  are  associated  with  marked 
hyperinosis.  In  children  the  specific  gravity  of  the  blood  is  usually 
high  during  the  febrile  period,  falling  to  normal  as  resolution 
takes  place;  in  cases  with  marked  cyanosis  the  concentration  of 
the  blood  also  raises  its  density.  Attempts  to  apply  the  serum  test 
in  this  disease  have  generally  been  disappointing,  most  reports 
having  shown  that  pneumococci  are  either  unaffected  by  the  serum 
of  pneumonia  patients  or,  at  the  most,  agglutinate  slowly  and 
atypically.  (See  p.  526.)  Rosenow,1  however,  reports  positive 
findings  in  77  of  83  cases  examined,  and  Huber 2  has  applied  the  test 
in  10  cases,  claiming  uniformly  positive  results,  the  reaction  ap- 
pearing as  early  as  the  fifth  day  of  the  disease,  increasing  in  inten- 
sity toward  crisis,  and  slowly  disappearing  by  about  the  tenth  day. 

Pneumonia,  like  enteric  fever,  is  an  example 
Bacteriology,  of  an  acute  infection  which  in  the  great  majority 
of  instances  must  be  classed  as  a  true  bacteriemia, 
even  in  its  early  stages.  With  modern  technic  it  is  now  possible 
to  culture  the  pneumococcus  from  the  circulating  blood  in  about 
70  per  cent,  of  all  cases  of  acute  pneumonia,  although  until  within 
recent  years  positive  bacteriological  findings  were  the  exception 

1  Medicine,  1903,  vol.  ix,  p.  435. 

2  Centralbl.  f.  inn.  Med.,  1902,  vol.  xxiii,  p.  417. 


506 


GENERAL  HEMATOLOGY. 


rather  than  the  rule.  Since  1900  the  following  statistics  have  been 
recorded:  Prochaska,1  50  cases,  all  positive,  with  12  deaths;  Rose- 
now,2  83  cases,  74  positive,  mortality,  45  per  cent.;  Silvestrini 
and  Sertoli,3  16  cases,  15  positive;  Pieracinni,4  28  cases,n  positive; 
Landi  and  Cionini,5  27  cases,  25  positive;  Kinsey,6  25  cases,  19 
positive,7  of  which  31  per  cent,  died;  and  Cole,8  30  cases,  9  positive, 
all  of  which  were  fatal.  In  contrast  with  these  figures  the  results  of 
the  earlier  investigators  should  be  compared.  Of  49  cases  studied 
by  Beco,9  7  were  positive,  with  5  deaths.  Sello,10  in  48  cases, 
found  12  positive  results,  of  which  10  ended  fatally.  Kraus 11  ex- 
amined 21  cases,  with  but  2  positive  findings,  both  in  fatal  cases. 

Franklin  W.  White,12  in  19  carefully  studied  cases  of  pneumonia, 
obtained  positive  results  in  3  patients,  all  of  whom  died;  of  the  16 
negative  cases,  7  proved  fatal.  Sittmann  13  found  the  pneumo- 
coccus  in  6  of  16  cases  examined  by  him,  in  4  cases  by  cul- 
tural methods,  and  in  2  in  stained  cover-slip  preparations  of  the 
blood;  of  these  6  positive  cases,  4  died,  and  of  the  10  negative 
cases  but  a  single  one  ended  fatally.  Kohn 14  examined  32  cases, 
obtaining  positive  results  in  9,  of  which  number  7  cases  were 
fatal,  while  the  other  2  finally  recovered  after  a  grave  infection; 
of  this  author's  23  negative  cases  recovery  took  place  in  8.  James 
and  Tuttle,15  in  their  studies  of  12  cases,  2  of  which  were  fatal, 
failed  in  every  instance  to  obtain  positive  findings. 

Analysis  of  the  above  data  affords  a  total  of  159  positive  findings 
in  which  the  outcome  of  the  disease  is  definitely  stated  by  the  ob- 
server, and  of  these  159,  96  ended  fatally — a  mortality  of  60.7 
per  cent.  It  is  obvious,  from  these  figures,  that  pneumococcemia, 
although  it  means  a  well-marked  infection,  is  by  no  means  a 
hopeless  sign,  as  was  once  believed. 

1  Centralbl.  f.  inn.  Med.,  1900,  vol.  xxi,  p.  1145;  also  Deutsch.  Arch.  f.  klin. 
Med.,  1901,  vol.  lxx,  p.  559. 

2  Loc.  cit.  3  Centralbl.  f.  allg.  Path.  u.  pathol.  Anat,  1900,  vol.  xi,  p.  447. 

4  Ibid.,  1900,  vol.  xi,  p.  460. 

5  Deutsch.  med.  Wochenschr.,  1901,  vol.  xxxvii,  p.  296. 

6  Jour.  Amer.  Med.  Assoc.,  1904,  vol.  xlii,  p.  759. 

7  The  proportion  of  bouillon  to  blood  in  this  series  was  15  or  20  to  1.  In 
another  series  of  25  cases,  with  a  6  :  1  dilution,  only  3,  or  12  per  cent.,  of  the  cultures 
were  positive. 

8  Johns  Hopkins  Hosp.  Bull.,  1902,  vol.  xiii,  p.  136. 

9  Rev.  de  med.,  1899,  vol.  xix,  pp.  385  and  461. 

10  Zeitschr.  f  klin.  Med.,  1898,  vol.  xxxvi,  p.  112. 

11  Zeitschr.  f.  Heilk.,  1896,  vol.  xvii,  pp.  117  and  138. 

12  Jour.  Exper.  Med.,  1899,  vol.  iv,  p.  425. 

13  Deutsch.  Arch.  I.  klin.  Med.,  1894,  vol.  Hii,  p.  323. 

14  Deutsch.  med.  Wochenschr.,  1897,  vol.  xxiii,  p.  136. 

15  Med.  and  Surg.  Rep.  of  the  Presbyterian  Hosp.,  New  York,  1898,  vol.  iii, 
p.  46. 


PNEUMONIA. 


During  the  active  stages  of  the  fever  the  hemo- 
Hemoglobin  globin  and  erythrocytes  are  either  normal  or 
and  very  slightly  diminished.  But  polycythemia  also 
Erythrocytes,  may  occur,  as  the  result  of  the  fever's  influence 
in  causing  contraction  of  the  peripheral  vessels, 
or  from  cyanosis.  During  the  post-febrile  period  moderately 
low  counts  are  usually  found,  being  due  possibly  to  the  hemo- 
cytolytic  effects  of  the  fever,  and  to  a  dilution  of  the  blood  caused 
by  the  decreased  arterial  tension  which  occurs  at  this  stage  of 
the  illness.  The  loss,  in  the  writer's  experience,  amounts  in  the 
average  case  to  about  20  per  cent,  of  the  normal  number  of  cells, 
with  a  slightly  greater  hemoglobin  decrease — approximately  25 
per  cent.  Poikilocytosis  and  other  structural  changes  in  the  cells 
are  to  be  noted  only  in  severe  cases.  In  109  hospital  cases  of 
croupous  pneumonia  the  hemoglobin  and  erythrocyte  values  were 
within  the  following  limits : 


Hemoglobin 
Percentage 


Number 
or  Cases. 


From  90-100  8 

"    80-  90  38 

"    70-  80  29 

"    60-  70  14 

"    50-  60  12 

"  40-  50----  7 
"    30-  40....  1 

Average,     75.0  per  cent. 

Maximum,  98.0 

Minimum,  26.0 


Erythrocytes  '  Number 

per  c.mm.  of  Cases. 

Above  5,000,000    3 

From  4,000,000-5,000,000  60 

"     3,000,000-4,000,000  41 

"     2,000,000-3,000,000  4 

"     1,000,000-2,000,000   1 

Average,     4,048,833  per  c.mm. 
Maximum,  5,070,000  "  " 
Minimum,  1,880,000  "  " 


In  pneumonia,  as  in  other  acute  infections,  the 
Leucocytes,  severity  of  the  infective  process  and  the  intensity 
of  the  reaction  on  the  part  of  the  organism  are 
the  factors  which  determine  the  behavior  of  the  leucocytes.  In 
the  great  majority  of  cases  a  well-marked  leucocytosis  develops 
at  or  soon  after  the  time  of  the  initial  chill,  and  persists  until 
shortly  after  the  temperature  has  fallen  to  normal. 

A  high  leucocytosis  indicates  a  severe  infection  in  an  indi- 
vidual of  strong  resisting  powers.  A  moderate  increase  indicates 
either  a  slight  infection  coupled  with  good  resistance,  or  an  in- 
tense infection  with  an  inadequate  reaction.  Little  or  no  leuco- 
cyte increase  also  suggests  one  of  two  diametrically  opposite  con- 
ditions :  either  an  infection  too  trivial  to  excite  reaction,  or  one  so 
severe  as  to  overpower  the  organism,  stifling  reaction.  Ewing1 

*N.  Y.  Med.  Jour.,  1893,  vol.  lviii  p.  715. 


5oS 


c.knkral  ih«:matoix)(;y. 


has  found  that,  as  a  rule,  the  increase  is  greater  in  cases  with 
extensive  lung  involvement  than  in  those  with  limited  lesions,  but 
this  parallelism  between  the  degree  of  leucocytosis  and  the  extent 
of  the  pneumonic  process  is  approximate,  and  does  not  always 
hold  good.  In  a  general  sense  it  applies  only  to  cases  which 
react  well  toward  the  disease.  There  is  no  relationship  between 
the  degree  of  increase  and  the  degree  of  fever  during  the  active 
stages  of  pneumonia. 

In  the  average  well-marked  case  the  number  of  leucocytes 
usually  ranges  between  20,000  and  30,000  per  c.mm.,  the  latter 
figure  being  only  rarely  exceeded,  as,  for  example,  in  severe  sthenic 
cases,  in  which  the  count  may  rise  to  40,000  or  50,000,  or  even 
higher.  To  illustrate  the  constancy  of  leucocytosis  in  pneumonia 
the  table  given  below  shows  that  this  sign  developed  in  about  two- 
thirds  of  the  153  cases  examined.  Summing  up  a  total  of  470  cases 
reported  by  various  observers,  it  is  found  that  the  average  "first 
count "  of  the  leucocytes,  during  the  febrile  stage  of  the  disease,  was 
22,693,  this  figure  applying  to  all  cases,  both  with  and  without 
leucocytosis.  In  the  writer's  experience  the  average  has  been 
distinctly  lower — 16,066  per  c.mm.  Absence  of  leucocytosis  is  of 
unfavorable  prognosis,  except  in  patients  in  whom  the  clinical 
type  of  the  infection  is  obviously  mild.  The  occurrence  of  a  high 
leucocytosis  is  of  no  definite  prognostic  value,  since  it  indicates 
simply  a  marked  infection  and  good  resisting  powers. 

The  following  table  shows  the  range  of  the  leucocytes  in  153 
hospital  cases  of  pneumonia : 

Leucocytes  per  c.mm.  Number  of  Cases. 

Above  50,000   1 

From  40,000-50,000  4 

30,000-40,000   2 

1 1      20,000-30,000  24 

"      15,000-20,000  35 

"      10,000-15,000  34 

5,000-10,000  49 

Below    5,000   4 

Average,     16,066  per  c.mm. 

Maximum,  83,600   "  " 

Minimum,    3,200   "  " 

To  these  figures  may  be  added  the  counts  made  in  10  cases 
of  catarrhal  pneumonia,  which  ranged  between  8000  and  40,000, 
and  averaged  15,210  per  c.mm.  Seven  of  the  cases  showed  definite 
leucocytosis — namely,  a  count  exceeding  10,000. 

In  cases  terminating  by  crisis  the  leucocytes  begin  to  diminish 


PNEUMONIA. 


5°9 


either  a  short  time  before  or  after  the  temperature  commences 
to  decline,  the  normal  number  being  reached,  in  most  cases,  within 
twenty-four  or  forty-eight  hours  after  crisis  occurs,  although  in  a 
small  proportion  of  cases  the  decrease  is  much  slower,  the  count 
sometimes  not  reaching  normal  until  a  week  after  the  tempera- 
ture has  dropped.  False  crises,  although  they  may  cause  a  striking 
drop  in  the  temperature,  do  not  cause  a  decline  of  the  leucocyte 
curve. 

In  cases  ending  by  lysis  the  decrease  in  the  number  of  leucocytes 
and  the  decline  in  the  temperature  begin  simultaneously,  but 
the  latter  reaches  normal  much  more  rapidly  than  the  former;  the 
leucocyte  decrease  progresses  more  gradually  than  in  the  cases 
ending  by  crisis,  and  the  normal  count  is  often  not  reached  until 
a  week  or  ten  days  after  the  temperature  has  fallen  to  the  normai 
figure.  At  the  beginning  of  lysis  a  correspondence  may  be 
distinguished  between  the  diurnal  fluctuations  of  the  temperature 
and  leucocyte  curves,  although  no  such  relation  is  apparent  during 
the  febrile  period  of  the  disease. 

It  is  an  interesting  fact  that  in  about  half  of  all  cases,  whether 
ending  by  crisis  or  by  lysis,  the  maximum  count  of  leucocytes  is 
attained  during  the  period  of  temperature  decline. 

Von  Jaksch's  1  idea  of  injecting  substances  to  cause  leuco- 
cytosis  in  pneumonia  where  this  phenomenon  was  absent,  hoping 
thereby  to  benefit  the  patient,  has  not  been  attended  by  the  favor- 
able results  which  he  anticipated.  Leucocytosis  is  as  promptly 
induced  in  the  pneumonic  as  in  the  healthy  individual,  by  the 
injection  of  nuclein,  for  example,  but  without  beneficial  effect 
upon  the  patient's  condition,  a  fact  which  must  be  regarded  as 
evidently  signifying  that  an  absence  of  leucocytosis  in  fatal  cases 
is  not  the  cause  of  death,  as  Billings2  remarks.  Borini3  injected 
digitalis  and  aleuron  into  rabbits  inoculated  with  virulent  pneu- 
mococci,  and  found  that  the  animals  treated  with  digitalis  sur- 
vived the  infection  longer  than  those  to  which  aleuron  was  given. 
Both  substances  caused  leucocytosis,  but  that  excited  by  aleuron 
was  transient,  while  that  caused  by  digitalis  persisted  for  some 
time — a  fact  to  which  Borini  believes  the  beneficial  effects  of 
digitalis  in  the  treatment  of  pneumonia  are  largely  due.  In  a  series 
of  German  Hospital  cases  reported  by  J.  C.  Wilson  4  the  injec- 
tion of  antipneumococcus  serum  was  followed  by  a  marked  increase 
in  the  number  of  leucocytes,  though  his  method  of  treatment  did 
not  perceptibly  lower  the  mortality. 

1  Cited  by  Cabot,  loc.  cit.       2  Johns  Hopkins  Hosp.  Bull.,  1894,  vol.  v,  p.  112. 

3  Centralbl.  f.  Bakt.  u.  Parasit,  1902,  vol.  xxxii,  p.  207. 

4  Jour.  Amer.  Med.  Assoc.,  1900,  vol.  xxxv,  p.  595. 


GENERAL  HEMATOLOGY. 


Hare 1  has  drawn  attention  to  the  fact  that  while  leucocytosis 
is  checked  by  antipyretics,  it  is  not  arrested  by  cold  sponging,  an 
observation  which  prompts  Cabot2  to  declare  in  favor  of  the  latter 
method  of  reducing  temperature  in  pneumonia. 

The  leucocytosis  of  pneumonia  is  of  the  typical  variety— that  is, 
it  is  due  to  a  large  absolute  and  relative  *  increase  in  the  poly- 
nuclear  neutrophiles,  with  a  consequent  relative  decrease  in  lym- 
phocytes. The  proportion  of  eosinophiles  is  much  reduced,  and 
frequently  these  cells  are  entirely  wanting.  This  is  regarded  as 
an  unfavorable  sign  by  Becker,3  who  states  that  he  has  never 
found  eosinophiles  in  fatal  cases.  It  is  of  interest  to  contrast  with 
this  circulatory  poverty  in  eosinophiles  the  great  abundance  of  these 
cells  in  serous  blister  fluid  of  pneumonia  patients,  as  determined  by 
Audibert.4  In  27  cases  of  various  diseases  this  observer  found  the 
highest  percentages  of  eosinophiles  in  pneumonia — much  higher, 
for  example,  than  in  pleurisy,  phthisis,  influenza,  rheumatic  fever, 
or  erysipelas.  With  the  decline  of  the  temperature  and  the 
fading  away  of  the  leucocytosis,  the  percentage  of  polymorphous 
cells  rapidly  falls  to  normal  or  subnormal,  and  the  lymphocytes 
and  eosinophiles  increase  until  they  regain  their  normal  percen- 
tages. The  latter  cells  usually  begin  to  reappear  in  the  circulation 
a  day  or  two  before  defervescence,  and  in  some  instances  a  striking 
post-febrile  eosinophilia  develops.  In  20  cases  showing  marked 
leucocytosis,  Billings  found  the  following  averages :  lymphocytes, 
9.6  per  cent. ;  polynuclear  neutrophiles,  91 .2  per  cent. ;  eosinophiles, 
0.2  per  cent.  Heim 5  found  a  similar  degree  of  polynuclear  neutro- 
phile  increase  in  19  cases.  In  3  of  Billings'  counts  in  fatal  cases 
showing  no  leucocytosis  it  was  found  that  the  various  forms  of 
leucocytes  remained  in  their  normal  relative  proportions.  The 
leucocytes  usually  respond  to  the  iodin  reaction,  most  strikingly,  in 
cases  with  high  leucocytosis.  In  such  instances  myelocytes  are 
generally  numerous. 

In  the  pneumonias  of  children  the  possibility  of  lymphocytosis 
should  be  remembered,  for  although  a  true  lymphocytosis  is  rare, 
it  sometimes  occurs,  giving  rise  to  false  impressions  if  clinical 
signs  other  than  the  examination  of  the  blood  are  neglected.  (See 
P-  253.) 

During  the  period  of  fever  the  blood  plaques  are  markedly  de- 
creased in  number,  and  often,  indeed,  altogether  disappear  from 
the  blood,  but  after  the  crisis  they  reappear  in  great  abundance, 

1  Therapeutic  Gaz.,  1898,  vol.  xii,  p.  153. 

2  Loc.  cit.  ^  3  Deutsch.  med.  Wochenschr.,  1900,  vol.  xxvi,  p.  558. 

4  Presse  med.,  1902,  vol.  xv,  p.  1256. 

5  Arch,  de  med.  des  Enf.,  1901,  vol.  iv,  p.  21. 


POISONING. 


the  fresh  specimen  taken  at  this  time  often  being  flooded  with 
these  bodies. 

In  atypical  cases  the  presence  of  a  well- 
Diagnosis.  marked  leukocytosis  is  a  helpful  sign  in  exclud- 
ing such  conditions  as  serous  pleurisy,  enteric 
fever,  typhus  fever,  malarial  fever,  and  influenza.  In  the  differ- 
entiation of  croupous  from  catarrhal  pneumonia,  empyema,  and 
acute  meningitis  the  leucocyte  count  furnishes  no  tangible  clue, 
since  it  is  high  in  all  these  conditions;  the  same  is  true  of  some 
cases  of  acute  bronchitis.  An  acute  apical  pneumonia,  if  associ- 
ated with  leucocytosis,  is  almost  invariably  to  be  considered  non- 
tuberculous. 

As  previously  stated,  absence  of  leucocytosis  in  a  case  with  well- 
defined  chest  signs  is  of  a  grave  prognosis,  but  the  presence  of  a 
leucocytosis  is  by  no  means  always  of  good  augury.  Persistence 
of  a  high  leucocyte  count  is  suggestive  of  delayed  resolution, 
empyema,  or  gangrene,  and  a  sudden  reestablishment  of  the 
leucocytosis,  after  its  disappearance  at  the  time  of  crisis,  points  to  a 
recurrent  attack  of  the  disease.  Reappearance  of  the  eosinophiles 
and  disappearance  of  the  iodin  reaction  indicate  the  termination 
of  the  acute  phase  of  the  illness.  Post- critical  iodophilia  is  most 
suggestive  of  delayed  resolution  or  of  a  more  serious  pulmonary 
sequela. 

Detection  of  the  pneumococcus  in  the  peripheral  circulation 
indicates  a  severe  infection,  but  it  is  not  per  se  &  grave  prognostic 
sign. 

LX.  POISONING. 

A  synopsis  of  the  blood  changes  produced  by  various  toxic 
substances  is  given  in  the  following  table,  these  changes  consist- 
ing chiefly  in  hemocytolysis,  methemoglobinemia,  anemia,  poly- 
cythemia, and  leucocytosis. 


Name  of  Poison.  Effects  upon  the  Blood. 

Alcohol  Anemia;  often  leucocytosis.1 

Amyl  nitrite  Methemoglobinemia.2 

Acetanilid  Marked  anemia,  with  many  erythro- 

blasts  and  stroma  degeneration;  leu- 
cocytosis ;  increase  of  plaques  ;3  eosino- 
philia  ;4  methemoglobinemia.5 

1  Cabot,  loc.  cit.  2  Grawitz,  loc.  cit. 


3  Stengel  and  White,  Univ.  of  Penna.  Med.  Bull.,  1903,  vol.  xv,  p.  462. 

4  Leredde  and  Pautrier,  Sem.  med.,  1903,  vol.  xxx,  p.  224. 

5  Muller,  Deutsch.  med.  Wochenschr.,  1887,  vol.  xiii,  p.  27. 


512  GENERAL  HEMATOLOGY. 

Name  of  Poison.  Effects  upon  the  Blood. 

Ammonia  Lcucocytosis.1 

Antipyrin  Methemoglobinemia.2 

Arseniuretted  hydrogen. .  .Hemoglobinemia.3 

Aspidium  Hemocytolysis.4 

Bromin  Methemoglobinemia.5 

Carbon  monoxid  Methemoglobinemia;    diminution  of 

oxygen  content;6  polycythemia;  leu- 
cocytosis;  carbonyl  hemoglobin.7 

Chloral  Leucocytosis . 1 

Chloroform  Oligochromemia ;  leucocytosis ; 8  oligo- 
cythemia; 9  diminished  alkalinity.10 

Chromic  acid   Methemoglobinemia.3 

Corrosive  metallic  salts. .  .Anemia;  leucocytosis.1 

Ether  r  Oligochromemia;  leucocytosis.11 

Fusel  oil  Hemocytolysis;  methemoglobinemia.12 

Guaiacol  Hemocytolysis;   leucocytosis;  relative 

lymphocytosis.13 

Hydrocyanic  acid  Methemoglobinemia.14 

Iodin  Methemoglobinemia.5 

Lead  Anemia;   granular   basophilia;  often 

leucocytosis.15 

Nitrobenzene  Methemoglobinemia;  megaloblastic  an- 
emia;16 eosinophile  leucocytosis.17 

Nitroglycerin  Methemoglobinemia.3 

Opium   Occasionally  leucocytosis.1 

Phenacetin  Methemoglobinemia. 18 

Phosphorus   Polycythemia;  occasionally  leucocyto- 
sis;19 slow  coagulability.20 

Potassium  chlorate  Methemoglobinemia;  anemia;  leucocy- 
tosis.21 

1  Cabot,  lac.  cit.  2  Miiller,  loc.  cit.  3  Grawitz,  loc.  cit. 


4  Georgiewsky,  Beitr.  z.  path.  Anat.  u.  z.  allg.  Path.,  1898,  vol.  xxiv,  p.  1. 

5  Hayem,  Compt.  rend.  Soc.  biol.,  Paris,  1886,  vol.  cii,  p.  698. 

6  Lacassagne,  Martin,  and  Nicloux,  Sem.  med.,  1903,  vol.  xxiii,  p.  25. 

7  Yarrow,  Amer.  Med.,  1904,  vol.  iv,  p.  338. 

8  Holman,  Jour.  Amer.  Med.  Assoc.,  1902,  vol.  xxxix,  p.  939. 

9  Loewy  and  Paris,  Compt.  rend.  Soc.  biol.,  Paris,  1902,  vol.  liv,  p.  188. 

10  Baccarani,  Gaz.  degli  Osped.  e.  d.  Clin.,  1900,  vol.  xlii,  p.  445. 

11  DaCosta  and  Kalteyer,  Annals  of  Surg.,  1901,  vol.  xxxiv,  p.  329. 

12  Futcher,  Amer.  Med.,  1901,  vol.  ii,  p.  210. 

13  Wyss,  Deutsch.  med.  Wochenschr.,  1894,  vol.  xx,  p.  296. 
14Kobert,  "Lehrb.  d.  Intoxicationen,"  Stuttgart,  1893. 

15  Grawitz  and  Hamel  Deutsch.  Arch.  f.  klin.  Med.,  1900,  vol.  lxvii,  p.  357 

16  Ehrlich  and  Lindenthal,  Zeitschr.  f.  klin.  Med.,  1896,  vol.  xxx,  p.  427. 

17  Personal  observation. 

18  Kronig,  Berlin,  klin.  Wochenschr.,  1898,  vol.  xxxii,  p.  998. 

19  Von  Jaksch,  Deutsch.  med.  Wochenschr.,  1893,  vol.  xix,  p.  10. 
20Cevidalli,  Phila.  Med.  Jour.,  1903,  vol.  xi,  p.  248. 

21  Bradenburg,  Berlin,  klin.  Wochenschr.,  1895,  vol.  xxxii,  p.  583. 


KABIKS. 


Name  of  Poison.  Effects  upon  the  Blood 

Potassium  permanganate .  Methemoglobinemia.1 

Ptomains   Leucocy tosis . 2 

Pyrodin   Hemocytolysis.3 

Pyrogallol  Methemoglobinemia.4 

Snake  and  scorpion  venom .  Hemoglobinemia ; 5    agglutination  of 

erythrocytes ; 6  diminished  coagula- 
lation;7  leucocytosis.8 

Sodium  nitrite  Methemoglobinemia.4 

Tansy   Leucocytosis.2 

Toadstools  Hemoglobinemia.9 

Toluene   Hemoglobinemia . 10 

Toluylendiamin  Marked  anemia ;  hemocytolysis ;  eosino- 
phil leucocytosis;  increase  of 
plaques.11 

Turpentine  Methemoglobinemia.12 


LXI.  RABIES. 

Courmont  and  Lesieur13  have  determined  that  an  exces- 
sive increase  in  the  number  of  polynuclear  neutrophiles  is  a 
constant  change  in  the  blood  of  patients  suffering  from  hydro- 
phobia, and  that  analogous  findings  are  met  with  experimentally 
in  rabid  dogs,  guinea-pigs,  and  rabbits.  The  polynuclear  gain  is 
frequently,  but  not  invariably,  associated  with  an  increase  in  the 
total  number  of  leucocytes.  It  may  amount  to  as  much  as  98 
per  cent.,  and  first  develops  during  the  period  of  incubation,  be- 
coming emphasized  with  the  appearance  of  the  clinical  symptoms 
of  the  affection,  and  reaching  a  maximum  just  before  death. 
The  authors  referred  to  believe  that  an  absence  of  polynucleosis 
is  sufficient  to  rule  out  rabies  in  a  suspected  case,  although  its 
presence  cannot  be  regarded  as  pathognomonic  of  the  disease. 

I  Hayem,  loc.  cit.  2  Cabot,  loc.  cit. 

3  Tallquist,  "Exper.  Blut-gift  Anamie,"  Berlin,  1900.  4  Grawitz,  loc.  cit. 

5  Mitchell  and  Stewart,  "A  Contribution  to  the  Study  of  the  Effect  of  the 
Venom  of  Crotalus  adamanteus  upon  the  Blood,"  Washington,  1898;  also  Rogers, 
Lancet,  1904,  vol.  i,  p.  349.  (As  a  rule,  colubrine  venoms  causes  slighter  blood 
destruction  than  those  of  the  viperine  type.  According  to  Elliot  [Lancet,  1904, 
vol.  ii,  p.  143],  the  venom  of  the  common  krait  causes  neither  hemolysis  nor  ab- 
normal clotting.) 

6  Flexner  and  Noguchi,  Proc.  Phila.  Path.  Soc,  1903,  vol.  vi,  p.  88. 

7  Lamb,  Glasgow  Med.  Jour.,  1903,  vol.  lix,  p.  80. 

8  Auche  and  Vaillant,  Jour,  de  Med.  de  Bordeaux,  1901,  vol.  xxxi,  p.  29. 

9  Kobert,  loc.  cit.  10  Vast,  These  de  Paris,  1889. 

II  Schwalbe  and  Solley,  Virchow's  Arch.,  1902,  vol.  clxviii,  p.  399. 

12  Hayem,  loc.  cit.  13  Sem.  med.,  1901,  vol.  xxi,  p.  61. 

33 


5i4 


GENERAL  HEMATOLOGY. 


LXII.  RELAPSING  FEVER. 

The  specific  cause  of  relapsing  fever,  a  spiril- 
Parasitology.  lum  discovered  by  Obermeier  in  1868/  may  be 
found  in  the  peripheral  blood  of  patients  suffer- 
ing from  this  disease,  only  during  and  shortly  before  the  febrile 
paroxysm,  the  organism  disappearing  from  the  general  circulation 
during  the  interparoxysmal  afebrile  period.  The  number  of  para- 
sites found  in  a  blood  film  varies  within  wide  limits,  and  does  not 
generally  stand  in  any -definite  parallelism  to  the  severity  of  the 
infection  or  to  the  degree  of  pyrexia. 

Microscopically,  the  spirilla  of  Obermeier  appear  in  the  fresh 


Fig.  63. — Spirilla  of  Relapsing  Fever. 


blood  as  delicate,  homogeneous,  thread-like  bodies  twisted  into 
the  form  of  spirals,  occurring  singly  or  in  groups  of  several  or- 
ganisms, radiating  from  a  common  center  (Fig.  63).  The  length 
of  the  parasites  varies  from  16  to  40  fi,  or  approximately  from  two 
to  six  times  the  size  of  the  normal  erythrocyte.  They  possess  an 
active  vibratile  motility,  exerted  in  the  direction  of  their  long  axes, 
by  virtue  of  which  they  are  propelled  and  constantly  altered  in 
shape.  Owing  to  this  characteristic  motility  the  presence  of  the 
parasites  is  usually  first  betrayed  to  the  examiner  by  the  whipping 
about  of  the  blood  corpuscles  in  their  immediate  proximity.  The 
spirilla  remain  alive  for  only  a  short  time  after  the  withdrawal 
of  the  blood,  and  are  so  extremely  sensitive  to  external  influences 
that  the  addition  even  of  distilled  water  causes  them  rapidly  to 

1  Centralbl.  f.  d.  med.  Wissensch..  1873,  vol.  xi,  p.  145. 


RELAPSING  FEVER. 


5^5 


disappear.  Since  nothing  is  known  of  their  life  history,  the  cause 
of  their  disappearance  from  the  peripheral  circulation  during  the 
intermissions  of  the  disease  is  not  known. 

Both  Sarnow1  and  von  Jaksch2  have  called  attention  to  the 
presence  of  certain  refractive  bodies,  similar  to  diplococci,  which 
may  be  found  in  the  blood  during  the  intermission,  provided  that 
another  paroxysm  is  impending.  The  last-named  authority  be- 
lieves that  he  has  observed  the  metamorphosis  of  these  bodies 
into  short  thick  rods  from  which  the  typical  spirilla  eventually 
are  evolved,  and  he  tentatively  regards  ^them  as  spores  of  the 
latter.  The  views  of  this  investigator  have  not,  however,  been 
generally  accepted  up  to  the  present  time. 

Afanassiew3  has  described,  in  addition  to  the  specific  spirilla, 
peculiar  bacteria  which  he  found  in  the  blood  during  the  parox- 
ysm. The  organisms  in  question  resemble  bacilli  with  rounded 
poles,  and  appear  to  be  invested  by  non-staining,  hyaline  sheaths. 
Some  of  them  measure  not  more  than  5  or  6  /jl  in  length,  while 
others  appear  as  filamentous  threads  fully  10,  12,  or  14  p.  long, 
this  increase  in  size  being  demonstrable  in  the  fresh  specimen 
watched  for  some  time  under  the  microscope.  Afanassiew  asserts 
that,  unlike  Obermeier's  spirilla,  the  bodies  may  be  cultivated  on 
bouillon,  gelatin,  agar,  and  blood  serum;  he  further  claims  that, 
in  three  patients  inoculated  with  a  twenty-four-hour-old  bouillon 
culture  of  the  organism,  periods  of  pyrexia,  recurring  at  ten-day 
intervals,  were  produced,  and  that  in  the  blood  of  one  of  the 
patients  thus  treated  numerous  bacillary  and  filamentous  forms 
were  discovered.  These  investigations,  as  yet  unconfirmed  by 
other  workers,  are  to  be  regarded  only  in  the  light  of  an  interesting 
observation. 

Melanin  granules,  either  free  or  within  the  protoplasm  of  the 
leucocytes,  are  frequently  seen  in  the  blood,  especially  just  after 
a  paroxysm,  and  phagocytes  containing  engulfed  spirilla  may  also 
be  found  at  this  time. 

Technic  of  Examination. — Fresh  specimens  of  blood,  taken 
during  the  paroxysm,  from  the  patient's  finger  or  ear,  are  most 
suitable  for  microscopical  examination.  The  motility  and  finer 
structure  of  the  spirilla  are  seen  most  clearly  with  a  y^-inch  oil- 
immersion  objective,  but  for  making  the  preliminary  search  a  lower 
power,  dry  lens  is  more  convenient,  a  f-  or  J-inch  objective  being 
useful  for  this  purpose. 

Dried  films,  fixed  by  one  of  the  chemical  methods  of  fixation 

1  Inaug.  Dissert.,  Leipsic,  1882. 

2  "Clinical  Diagnosis,"  3d  ed.,  London  and  Philadelphia,  1897,  p.  50. 

3  Centralbl.  f.  Bakt.  u.  Parasit.,  1899,  vol.  xxv,  p.  273. 


GENERAL  HEMATOLOGY. 


already  described  (p.  80),  may  be  stained  preferably  by  fuchsin, 
or  the  method  of  Gunther  (p.  112)  may  be  used.  For  diagnostic 
purposes  stained  specimens  are  never  to  be  preferred  to  the  fresh 
blood  film. 

LowentkaVs  Reaction. — The  ingenious  blood  test  devised  by 
Lowenthal 1  furnishes  a  means  of  recognizing  relapsing  fever  dur- 
ing the  afebrile  period,  when  the  spirilla  cannot  be  detected  in  the 
blood.  It  is  conducted  in  the  following  manner:  A  drop  of 
blood  from  a  suspected  case  is  mixed  with  a  drop  containing 
motile  spirilla,  the  latter  being  taken  from  a  patient  during  the 
paroxysmal  stage  of  the  disease.  The  mixture  thus  made  is 
sealed  between  a  slide  and  cover-glass,  and  incubated  at  body 
temperature  for  half  an  hour,  at  the  end  of  which  time  it  is  ex- 
amined under  the  microscope.  If  the  suspected  case  is  one  of 
relapsing  fever,,  the  spirilla  will  have  become  quite  motionless  and 
collected  together  in  regular  masses,  while  if  the  case  is  one  of 
some  other  disease,  the  motility  of  the  parasites  remains  unim- 
paired. A  control  specimen,  prepared  from  normal  and  spirilla- 
containing  blood,  must  always  be  similarly  incubated  and  ex- 
amined with  each  test.  If  no  such  reaction  as  that  described 
occurs  within  a  time  limit  of  two  hours  and  one-half  at  the  most, 
it  is  safe  to  regard  the  suspicious  case  as  one  not  of  relapsing 
fever.  In  35  cases  of  this  disease  Lowenthal  obtained  about  85 
per  cent,  of  positive  results,  while  in  14  cases  of  fever  due  to  other 
causes  the  reaction  was  uniformly  absent. 

The  reaction,  which  takes  place  in  abortive  and  mild  cases  as 
well  as  in  the  severer  forms  of  the  disease,  is  thought  to  be  de- 
pendent upon  the  presence  in  the  blood  of  specific  bactericidal 
products. 

Von  Limbeck,2  quoting  von  Bockmann,  states 
Hemoglobin  that  there  is  a  decrease  in  the  number  of  erythro- 
and         cytes  and  in  the  hemoglobin  value  in  cases  of  re- 
Erythrocytes.  lapsing  fever,  but  neither  the  mode  of  production 
of  such  an  anemia  nor  the  exact  morphological 
changes  by  which  it  is  characterized  has  been  carefully  investi- 
gated, so  far  as  can  be  ascertained.    The  losses  are  observed  to 
occur  during  and  for  a  few  days  after  each  paroxysm,  but  they 
are  partly  compensated  during  the  interparoxysmal  period. 

A  variable  degree  of  increase  in  the  number  of 
Leucocytes,  leucocytes,  often  of  high  grade,  has  been  described 
by  Laptschinski3  as  associated  with  the  paroxys- 
mal stage  of  the  disease,  this  observer  having  noted  that  the  poly- 

1  Deutsch.  med.  Wochenschr.,  1897,  vol.  xxiii,  p.  560. 

2  Loc.  cit.  y  Centralbl.  f .  d.  med.  Wissensch.,  1875  vol.  xiii,  p.  36. 


RELAPSING  FEVER. 


517 


nuclear  neutrophiles  were  especially  involved,  and  that  the  relative 
number  of  leucocytes  to  erythrocytes  was  in  some  instances  as 
high  as  1  to  37.  During  the  period  of  intermission  this  leucocytosis 
disappears.  This  author,  as  well  as  von  Bockmann1  and  Heiden- 
reich,2  also  noted  that  the  period  of  maximum  leucocytosis  was 
reached  just  after  the  crisis.  Melkich,3  in  14  cases  of  spirillum 
fever,  noted  that  the  highest  counts  were  attained  twenty-four 
hours  before  the  crisis,  after  which  the  leucocytosis  persisted  for 
a  day  or  two  and  then  rapidly  declined,  the  effect  of  each  succeeding 
relapse  being  to  accentuate  this  post-critical  hypoleucocytosis. 

The  same  worker,  in  collaboration  with  Kalyapin,4  also  de- 
termined that  in  this  infection  no  direct  relation  exists  between 
the  leucocyte  count  and  the  richness  of  the  blood  in  alexins. 
These  substances,  which  are  found  most  abundantly  during  the 
initial  paroxysm,  begin  to  diminish  just  before  the  crises,  still 
further  decrease  during  the  afebrile  periods,  and  again  increase 
with  the  febrile  recurrences.  With  convalescence  the  alexins  rise 
to  high  figures  and  remain  so  until  recovery  takes  place. 

Phagocytosis  occurs  with  great  constancy  in  the  peripheral 
blood.  Ivanoff,5  who  first  demonstrated  this  fact,  has  shown  that 
phagocytic  leucocytes  containing  fragments  of  spirilla  are  almost 
invariably  present  in  the  finger-blood  of  this  infection.  Espe- 
cially is  this  the  case  in  immunized  monkeys,  in  whose  blood 
intracellular  spirilla  are  the  rule  and  extracellular  spirilla  the 
exception. 

The  detection  of  the  spirillum  in  the  blood 
Diagnosis,  immediately  differentiates  relapsing  fever  from 
typhus  fever,  the  onset  and  initial  symptoms  of 
which  not  infrequently  prove  confusing,  and  it  may  also  be  added 
that  in  such  instances  the  absence  of  this  organism  during  the  stage 
of  pyrexia  is  strong  evidence  for  excluding  the  first-named  disease. 
During  the  afebrile  period,  when  the  symptoms  may  suggest,  for 
example,  malarial  fever,  Lowenthal's  reaction  should  be  attempted, 
and  the  malarial  parasite  searched  for.  Melanemia,  it  must  be 
recalled,  may  be  encountered  in  each  of  these  infections. 

1  Loc.  cit:  2  "Untersuch.  ii  d.  Par.  d.  Ruckfallstyphus,"  Berlin,  1877. 

3  Russkiy  Vrach,  1903;  abst.,  Med.  News,  1903,  vol.  lxxxiii,  p.  103 1. 

4  Ibid.  5  Centralbl.  f.  Bakt.  u.  Parasit.,  1897,  vol.  xxii,  p.  117. 


Si8 


GENERAL  HEMATOLOGY 


LXIII.  RHEUMATIC  FEVER. 

Coagulation  of  the  blood  takes  place  within  the 
General     normal  time  limit,  or  it  may  be  delayed  consider- 
Features.    ably.    The  amount  of  fibrin  is  markedly  in- 
creased, especially  during  the  most  acute  stages  of 
the  illness.    Contradictory  reports  have  been  made  by  different 
authors  concerning  the  alkalinity,  some  having  found  it  dimin- 
ished, and  others  having  been  unable  to  detect  any  such  altera- 
tion.   According  to  Hutchinson,1  the  general  consensus  of  opinion 
is  against  any  notable  disturbance  of  the  normal  figure.    In  chronic 
articular  rheumatism  with  coexisting  anemia  a  slight  diminution 
of  the.  alkalinity  is  occasionally  observed. 

The  bacteriology  of  the  blood  in  this  disease  has  for  many  years 
been  the  object  of  much  careful  study,  but  thus  far  specific 
properties  have  not  been  generally  conceded  to  any  definite 
organism,  although  many  different  bacilli,  streptococci,  staphylo- 
cocci, and  diplococci  have  been  cultivated  from  the  circulating 
blood  during  life.  Most  suggestive  are  the  investigations  of 
Paine  and  Poynton,2  who  discovered  a  micrococcus,  growing  in 
streptococcal  chains,  in  the  blood  of  18  cases  of  rheumatic  fever. 
This  organism  is  closely  allied  to,  if  not  identical  with,  that 
previously  described  by  Wasserman,3  Triboulet,4  and  others.  The 
same  micrococcus  has  been  cultured  by  Beaton  and  Walker5  in 
15  cases— 8  of  acute  rheumatic  fever,  4  of  rheumatic  endocarditis, 
and  3  of  chorea.  Rabbits  inoculated  with  this  organism  die 
after  developing  fever,  arthritides,  endocarditis,  pericarditis,  and 
sepsis,  and  from  their  cadavers  the  micrococcus  can  be  recovered 
in  pure  culture.  Shaw,6  who  recently  confirmed  the  above  find- 
ings, succeeded  in  carrying  out  two  successful  inoculation  experi- 
ments with  monkeys.  These  investigators  claim  to  have  differen- 
tiated this  "Micrococcus  rheuniaticus"  from  the  ordinary  Strepto- 
coccus pyogenes  (which  Singer 7  believes  to  be  the  germ  described) 
by  Marmorek's  method  of  culturing  it  upon  filtered  streptococcus - 
bouillon  in  which  streptococci  of  human  origin  fail  to  develop. 

1  Lancet,  1896,  vol.  i,  p.  615. 

2  Brit.  Med.  Jour.,  1900,  vol.  ii,  pp.  861  and  932;  also  ibid.,  1901,  vol.  ii, 
P-  779- 

Berlin,  khn.  Wochenschr.,  1899,  vol.  xxxvi,  p.  638. 

4  Rev.  de  med.,  Paris,  1888,  vol.  xviii,  pp.  189  and  329;  also  Triboulet,  Coyon, 
and  Zadoc,  Bull.  Soc.  med.  des  hop.  de  Paris,  1897,  vol.  xiv,  p.  1343;  also 
"Le  Rheumatisme  articulaire  aigu  en  bacteriologie,"  Triboulet  et  Coyon,  Paris, 
1900. 

5  Brit.  Med.  Jour.,  1903.  vol.  i,  p.  237;  also  Walker,  Practitioner,  1903,  vol. 
lxx,  p.  185. 

6  Jour.  Path,  and  Bact.,  1903,  vol.  ix,  p.  158.  7  Ibid.,  1901,  vol.  ii,  p.  780. 


RHEUMATIC  FEVER. 


519 


Additional  proof  of  the  specificity  of  this  organism,  together  with 
a  study  of  the  toxic  specificity  of  rheumatic  fever  and  of  the  mode 
of  infection,  is  necessary  before  the  organism  in  question  can 
be  universally  credited  as  the  exciting  factor  of  the  disease. 

Few  cases  of  acute  rheumatic  fever  are  unac- 
Hemoglobin  companied  by  anemia,  the  intensity  of  which 
and  generally  bears  a  fairly  close  relation  to  the  se- 
Erythrocytes.  verity  and  the  duration  of  the  illness.  In  acute 
attacks  of  short  duration  the  hemoglobin  falls  to 
about  70  or  80  per  cent,  and  the  erythrocytes  to  4,000,000,  but 
in  cases  of  longer  standing  the  losses  are  likely  to  be  more  pro- 
nounced, the  count  often  being  not  more  than  3,000,000  or  there- 
abouts. The  color  index  usually  is  moderately  subnormal,  and 
may  tend  to  remain  so  after  the  attack,  even  though  the  rise  nor- 
malward  of  the  erythrocyte  count  may  have  become  well  estab- 
lished. In  the  exceptional  case,  however,  it  may  be  quite  as  high 
as  in  pernicious  anemia;  in  4  of  32  cases  noted  below  the  index 
was  above  1.00.  In  chronic  rheumatism  a  moderate  oligo- 
chromemia  is  usually  the  only  evidence  of  anemia  that  can  be 
detected,  unless  the  patient  happens  to  be  decidedly  cachectic. 
In  the  writer's  experience,  the  erythrocytes  fall  below  3,000,000 
in  about  one  case  in  every  five;  in  an  occasional  case  the  anemia 
may  be  intense,  as  in  two  of  those  tabulated  below,  with  hemo- 
globin figures  of  26  and  30  per  cent,  and  counts  of  1,242,000  and 
1,590,000,  respectively.  In  the  following  table  of  32  cases  it  will 
be  noted  that  the  anemia  averages  greater  than  most  authors 
report : 

Hemoglobin  Number  Erythrocytes  Number 
Percentage.     oe  Cases.  per  c.mm.  of  Cases. 

From  90-100  3  From  4,000,000-5,000,000  16 

"    80-90  5  "    3,000,000-4,000,000  9 

"    70-80  7  "     2,000,000-3,000,000  5 

"    60-70  3  "     1,000,000-2,000,000  2 

"    50-60  8 

"    40-50  2 

"    30-40  o 

"    20-30  4 

Average,     63  per  cent.    Average,     3,686,648  per  c.mm. 

Maximum,  92      "  Maximum,  4,980,000  "  " 

Minimum,  26      "  Minimum,  1,242,000  "  " 

The  average  hemoglobin  percentage  in  33  cases  studied  by 
McCrae  1  was  73.4,  and  the  average  erythrocyte  count,  4,636,000. 

1  Amer.  Med.,  1903,  vol.  vi,  p.  22. 


520 


GENERAL  HEMATOLOGY. 


Cabot's  43  cases  1  averaged  67  per  cent,  of  hemoglobin  and  4,400,- 
000  erythrocytes  per  c.mm. 

Should  the  cellular  loss  reach  a  high  grade,  deformities  of 
shape  and  size,  polychromatophilia,  and,  rarely,  nucleated  erythro- 
cytes of  the  normoblastic  type,  may  be  observed. 

Leucocytosis  of  the  typical  polynuclear  neutro- 
Leucocytes.  phile  type  is  almost  always  present  during  the 
acute  stages,  but  it  is  found  only  exceptionally  in 
the  subacute  form  of  rheumatism,  and  practically  never  exists  in 
the  chronic  variety.  The  count  does  not  often  exceed  twice  the 
maximum  number  of  cells  found  normally,  but  occasionally  it 
reaches  a  figure  as  high  as  30,000  or  40,000  per  c.mm.  It  is  in 
cases  with  intense  pyrexia,  with  endocarditis  or  pericarditis,  and 
with  pulmonary  complications  that  high  leucocytoses  are  most 
commonly  found. 

In  32  cases  the  leucocyte  counts  ranged  as  follows: 

Leucocytes  per  c.mm.  Number  of  Cases. 

Above  20,000   2 

From  15,000-20,000    9 

"     10,000-15,000    8 

5,000-10,000   11 

Below  5,000   2 

Average,     12,218  per  c.mm. 
Maximum,  31,200  "  " 
Minimum,    4,800  " 


McCrae's  leucocyte  figures  in  36  cases  averaged  12,370,  and 
in  but  9  was  the  count  below  10,000  at  the  first  examination. 

In  Cabot's  cases,  above  referred  to,  the  number  of  leucocytes 
averaged  16,800,  and  ranged  from  4700  to  39,000. 

Turk  *  has  noticed  that  in  many  instances  well-marked  post- 
febrile eosinophilia  develops,  and  that  in  favorable  cases  a  relatively 
high  percentage  of  eosinophiles  persists  during  the  acute  stage  of 
pyrexia.  Both  Korowicki 3  and  Patella 4  describe  a  mononucleosis 
in  cases  with  endocarditis,  but  the  writer  has  been  unable  to  verify 
this  finding. 

The  blood  changes  are  uncharacteristic,  and 
Diagnosis,     do  not  serve  as  a  means  of  differentiating  this  con- 
dition from  other  lesions  in  which  the  joint  in- 
volvement and  the  constitutional  manifestations  are  more  or  less 

1  Loc.  cit.  2  £oc 

3  Deutsch.  Aerzte-Zeitung,  1903,  vol.  i,  p.  241. 

4  Sem.  med.,  1903,  vol.  xxiii,  p.  368. 


SCARLET  FEVER.  521 

similar.  Thus,  in  acute  gout,  in  multiple  secondary  arthritis,  and 
in  septic  arthritis  due  to  pyemia  the  same  grade  of  anemia,  leuco- 
cytosis,  and  hyperinosis  may  be  observed.  In  the  latter  condition 
blood  culturing  may  be  helpful.1  Iodophilia  means  gonorrheal 
arthritis  rather  than  rheumatic  fever.    (See  p.  228.) 


LXIV.  SCARLET  FEVER. 

In  cases  associated  with  pronounced  anginal 
General     symptoms  and  with  marked  leucocytosis  coagu- 
Features.     lation  of  the  fresh  blood  drop  is  rapid  and  the 
amount  of  fibrin  decidedly  in  excess  of  normal. 
In  many  cases  a  slight  increase  of  fibrin  is  observed  at  the  period 
of  beginning  desquamation. 

The  specific  gravity  is  unchanged  in  the  average  case,  but  in 
those  complicated  by  acute  parenchymatous  nephritis,  in  conse- 
quence of  the  drain  on  the  albumins  of  the  blood  thus  pro- 
duced, it  may  fall  to  a  very  low  figure — to  1 .030,  according  to 
Peiper  and  Hammerschlag.2  In  12  cases  studied  by  van  den 
Berg,3  the  specific  gravity  ranged  from  1.031  in  complicated  cases 
to  1 .060  in  uncomplicated  cases  of  the  average  severity. 

The  specific  micro-organism  of  scarlet  fever  has  not  yet  been 
isolated,  either  from  the  blood  or  other  tissues,  although  in  re- 
cent, years  many  different  bacteria  have  been  described  as 
causative  factors.  Class4  claims  to  have  discovered  in  the  blood 
and  throats  of  scarlet  fever  patients  a  diplococcus,  named  by  him 
the  Diplococcus  scarlatina,  which  he  considers  specific,  and  this 
claim  has  received  the  support  of  a  number  of  other  investigators, 
Gradwohl,5  Jaques,6  and  Page7  being  among  those  who  found  the 
bacterium  in  question.  Baginsky  and  Sommerfeld 8  conclude,  as 
have  some  earlier  writers,  that  the  clinical  features  of  scarlet  fever 
are  due  to  a  general  streptococcus  infection,  having  found  this 
organism  in  the  blood  of  42  fatal  cases.  Class,9  in  a  later  communi- 
cation, hints  that  his  diplococcus  and  Baginsky  and  Sommerfeld's 
streptococcus  are  identical,  since  the  former  often  develops  strep- 

1  See  articles  on  Pneumococcus  Arthritis  by  Herrick  (Amer.  Jour.  Med.  Sci. 
1902,  vol.  exxiv,  p.  12)  and  by  Cole  (Amer.  Med.,  1902,  vol.  iii,  p.  905). 

2  Centralbl.  f.  klin.  Med.,  189 1,  vol.  xii,  pp.  217  and  825. 

3  Arch.  f.  Kinderheilk.,  1898,  vol.  xxv,  p.  321. 

4  Med.  Rec,  1899,  vol.  lvi,  p.  330. 

5  Phila.  Med.  Jour.,  1900,  vol.  iv,  p.  688. 

6  Ibid.,  p.  552.  7  Jour.  Bost.  Soc.  Med.  Sci.,  1899,  vol.  iii,  p.  344- 

8  Berlin,  klin.  Wochenschr.,  vol.  xxxvii,  p.  588. 

9  Jour.  Amer.  Med.  Assoc.,  1900,  vol.  xxxv,  p.  799. 


522 


GENERAL  HEMATOLOGY. 


tococcus  forms  in  young  cultures  made  from  the  blood.  Any  one 
who  has  read  Class'  description  of  his  organism  must  be  struck 
with  its  resemblance  to  the  diplococcus  found  in  scarlet  fever 
blood  by  Crajkowski,1  in  1895.  Both  Hektoen2  and  Jochmann  3 
have  isolated  the  streptococcus  during  life  in  a  large  series 
of  scarlet  fever  patients,  the  former  in  12  per  cent,  and  the 
latter  in  15.5  per  cent,  of  cases  examined.  Hektoen's  findings 
suggest  no  definite  relationship  between  the  severity  of  the 
disease  and  the  presence  of  a  bacteriemia,  for  the  latter  may 
develop  in  mild,  uncomplicated  cases,  and  may  not  occur  in 
fatal  ones;  as  a  rule,  however,  more  colonies  grow  in  cul- 
tures made  from  severe  types  of  the  disease.  Jochmann  de- 
cides that  the  presence  of  a  streptococcemia  does  not  modify 
the  symptomatology  of  scarlet  fever;  excluding  those  dying  of 
nephritis,  one-half  of  his  fatal  cases  gave  cultures  of  the  strep- 
tococcus. Mackie  4  found  streptococci  and  staphylococci  in  3  of  6 
cases  by  blood  culturing  during  life.  From  the  findings  just  stated 
it  is  clear  that  streptococci  in  scarlet  fever  play  the  role  not  of  a 
specific  factor,  but  rather  of  a  secondary  infection,  the  relationship 
of  which  to  the  primary  infective  agent  remains  obscure.  The 
streptococci  found  in  scarlet  fever  cannot  be  differentiated  from 
ordinary  forms  of  this  organism;  and  the  immunity  conferred  by 
an  attack  of  scarlet  fever  protects  only  against  this  exanthema, 
and  not  against  ordinary  streptococcus  infections. 

Jehle 5  states  that  he  has  repeatedly  isolated  the  influenza 
bacillus  from  the  blood  of  young  children  ill  with  scarlet  fever. 
It  may  be  added  that  Mallory's  protozoa,6  found  in  the  skin  of 
scarlet  fever  patients,  have  not  been  demonstrated  in  the  circula- 
ting blood. 

Most  observers  agree  that  the  scarlatinal  infec- 
Hemoglobin  tion,  unless  complicated,  produces  but  trifling 
and         changes  in  the  hemoglobin  and  erythrocytes, 
Erythrocytes,  moderate  anemia  characterized  by  a  dispropor- 
tionate diminution  of  hemoglobin  being  the  gen- 
eral rule  in  the  cases  in  which  any  changes  are  noted. 

Widowitz  7  found  that  the  percentage  of  hemoglobin,  normal 
at  the  beginning  of  the  illness,  slowly  diminished  during  the  fe- 
brile period,  in  a  degree  commensurate  to  the  intensity  of  infec- 

1  Centralbl.  f.  Bakt.  u.  Parasit.,  1895,  vol.  xviii,  p.  116. 

2  Jour.  Amer.  Med.  Assoc.,  1903,  vol.  xl,  p.  685. 

3  Deutsch.  Arch.  f.  klin.  Med.,  1903,  vol.  lxxviii,  p.  209. 

4  Lancet,  1904,  vol.  i,  p.  494.  *  Zeitschr.  f.  Heilk.,  1901,  vol.  xxii,  p.  100. 
Boston  Soc.  Med.  Sci.,  Dec.  15,  1903;  also  Jour.  Amer.  Med.  Assoc.,  1004, 

vol.  xlu,  pp.  31  etseq.  y 
7  Jahrb.  f.  Kinderheilk.,  1888,  vol.  xxvii,  p.  380;  vol.  xxviii,  p.  25. 


SCARLET  FEVER. 


523 


tion,  and  gradually  returned  to  normal  during  convalescence. 
PeV  noticed  in  severe  cases  a  pronounced  "chloro-anemia," 
characterized  by  notable  pallor  and  variations  in  the  size  of  the 
corpuscles.    Hemoglobinemia  has  also  been  occasionally  observed. 

The  number  of  erythrocytes  is  generally  between  4,000,000 
and  5,000,000  per  c.mm.  in  the  case  of  average  severity,  the 
minimum  count  being  reached  at  about  the  time  of  the  decline 
of  the  temperature;  but  in  complicated  cases  the  anemia  is  more 
marked,  and  histological  degenerative  changes  of  the  corpuscles 
have  been  noted  during  the  period  of  desquamation.  Van  den 
Berg's  examinations  of  12  cases2  show  that  the  count  is  usually 
above  4,000,000  per  c.mm.,  except  in  severe  cases  complicated 
by  acute  nephritis  or  endocarditis,  in  the  event  of  which  a  rapid 
and  striking  anemia  is  produced,  the  hemoglobin  sometimes  being 
as  low  as  25  per  cent.,  and  the  corpuscles  diminishing  to  as  low 
as  2,000,000  per  c.mm.  In  addition  to  these  complications  severe 
streptococcus  septicemia  may  account  for  a  high  grade  of  scarla- 
tinal anemia.  From  an  analysis  of  the  cases  reported  by  Zappert,3 
Felsenthal,4  Widowitz,5  Hayem,6  and  others  the  average  loss  of 
erythrocytes  in  all  cases  amounts  to  about  1,000,000  cells  to  the 
c.mm.,  but  Kotschetkoff 7  notes  a  more  decided  average  reduction, 
this  author  stating  that  they  progressively  decrease  to  about 
3,000,000,  and  that  regeneration  is  slow  and  gradual,  not  being 
completed  for  a  period  of  six  weeks. 

A  well-marked  leucocytosis,  the  count  usually 
Leucocytes,  ranging  between  20,000  and  30,000  per  c.mm., 
occurs  in  the  majority  of  cases,  often  first  ap- 
pearing several  days  in  advance  of  the  cutaneous  eruption,  and 
persisting  in  some  cases  long  after  convalescence  has  been  estab- 
lished. Its  duration  varies  widely  in  different  instances :  in  some 
cases,  not  necessarily  of  a  severe  type,  the  leucocytosis  persists  for 
ten,  or  even  thirty,  days;  while  in  others,  usually  of  a  mild  type, 
it  disappears  before  the  temperature  has  fallen  to  normal.  The 
maximum  degree  of  increase  is  reached  from  four  to  six  days  after 
the  onset  of  the  illness. 

In  asthenic  cases  the  number  of  leucocytes  is  increased  but 
slightly,  or  not  at  all;  but  in  the  well-nourished  child  the  degree 
of  leucocytosis  may  be  regarded  as  a  rough  gage  of  the  intensity 
of  the  infection,  being  usually  greater  in  severe  than  in  mild  cases. 
The  increase  appears  to  bear  no  fixed  relationship  either  to  the 

1  Inaug.  Dissert.,  Berlin,  1890.  2  Log.  cit. 

3  Zeitschr.  f.  klin.  Med.,  1893,  vol.  xiii,  p.  292. 

4  Arch.  f.  Kinderheilk.,  1892,  vol.  xv,  p.  82.  5  Log.  cit. 

6  St.  Petersburg,  med.  Wochenschr.,  1892,  vol.  i,  p.  914. 

7  Russkiy  Vrach,  1891,  vol.  xii,  p.  919. 


524 


GENERAL  HEMATOLOGY. 


anginal  infection  or  to  the  glandular  involvement,  for  marked  leu- 
cocytosis  has  been  observed  in.  cases  with  mild  angina  unac- 
companied by  swelling  of  the  glands.  Neither  can  any  clear  re- 
lation be  established  between  the  leucocytosis  and  the  character 
of  the  temperature,  the  period  of  desquamation,  and  the  inflam- 
matory complications  of  the  ear  and  kidneys. 

In  all  of  van  den  Berg's  cases  the  number  of  leucocytes  was 
in  excess  of  normal,  the  " first  counts"  averaging  slightly  more 
than  17,000  per  c.mm.,  and  the  leucocytosis  being  higher  than 
30,000  in  only  2  cases.  The  investigations  of  the  other  authors 
above  referred  to  give  practically  the  same  results,  although 
somewhat  higher  counts  have  been  made  in  some  instances. 
Mackie1  found  leucocytosis  constant  in  25  cases,  and  in  one 
patient  with  severe  anginal  symptoms  the  count  rose  to  93,300. 
He  failed  to  observe  any  signs  of  a  leucocyte  increase  until  twenty- 
four  hours  after  the  appearance  of  the  rash. 

The  leucocytosis  is  generally  due  to  an  increase  in  the ,  poly- 
nuclear  neutrophils,  these  cells  ranging  from  85  to  90  per  cent. ; 
but  in  some  instances  the  increase  is  more  evenly  divided  between 
the  polymorphous  and  mononuclear  forms,  so  that  from  70  to 
80  per  cent,  of  the  former  and  from  15  to  30  per  cent,  of  the 
latter  may  be  found.  The  writer  has  noticed  the  presence  of 
large  numbers  of  the  so-called  transitional  mononuclear  leu- 
cocytes and  of  an  occasional  myelocyte.  Van  den  Berg  has  noted 
the  presence  of  small  numbers  of  myelocytes  in  grave  cases. 
Contrary  to  the  rule  which  holds  good  in  most  febrile  conditions, 
the  number  of  eosinophiles  in  favorable  cases  of  scarlet  fever 
remains  normal,  or,  indeed,  may  be  decidedly  increased.  In  the 
majority  of  favorable  cases  the  eosinophile  increase  begins  after  the 
patient  has  been  ill  two  or  three  days,  and  attains  a  maximum  during 
the  second  or  third  week,  after  which  it  progressively  diminishes, 
the  percentage  reaching  normal  by  about  the  sixth  week.  In 
very  grave  cases  a  decrease  or  absence  of  these  cells  is  usually 
found.  In  cases  with  nephritic  complications  their  increase  is 
thought  to  be  favorable.  The  proportion  of  eosinophiles  is 
usually  from  4  to  5  per  cent,  of  the  other  forms,  sometimes  even 
10  or  15  per  cent.,  especially  during  the  post-febrile  period  of 
the  disease.  Bowie,2  from  a  study  of  167  cases,  concludes  that 
normal  or  subnormal  eosinophile  values  after  the  first  forty- 
eight  hours  mean  a  severe  infection,  and  that  the  graver  the  case, 
the  longer  the  persistence  of  these  low  figures. 

The  blood  plaques  are  normal  at  the  beginning  of  the  attack, 

1  Lancet,  1901,  vol.  ii,  p.  525. 

2  Jour.  Path,  and  Bacteriol.,  1902,  vol.  viii,  p.  82. 


SEPTICEMIA  AND  PYEMIA. 


525 


but  a  large  increase  in  their  number  is  said  to  occur  during  the 
period  of  desquamation. 

The  presence  of  leucocytosis  and  persistence 
Diagnosis,    of  the  eosinophiles  are  suggestive  signs  in  distin- 
guishing scarlet  fever  from  measles,  since  in  un- 
complicated cases  of  the  latter  disease  these  changes  are  absent. 
Disappearance  of  the  eosinophiles  is  regarded  as  a  bad  prognos- 
tic sign. 

LXV.  SEPTICEMIA  AND  PYEMIA. 

The  blood  changes  found  in  those  conditions 
General     due  to  the  presence  in  the  circulating  blood  of 
Features,     septic  bacteria  or  their  toxins,  general  septicemia, 
sa pyemia,  and  pyemia,  are  similar,  and  therefore 
may  be  considered  together  under  the  above  heading.    An  ap- 
parently trivial  infected  wound  may  give  rise  to  just  as  severe 
blood  changes  as  an  intense  pyemia  with  wide-spread  metastatic 
abscesses,  since  these  alterations  depend  upon  the  virulence 
of  the  infection  and  the  reaction  which  it  provokes,  rather  than 
upon  the  character  of  the  exciting  lesion  and  the  specific  nature  of 
the  offending  organisms.    Clinically,  these  blood  changes  may  be 
associated  with  such  conditions  as  infected  wounds,  osteomyelitis, 
malignant  endocarditis,  puerperal  fever,  septic  joints,  and  many 
other  lesions  for  which  various  septic  micro-organisms  are  held 
responsible. 

The  amount  of  fibrin  is  often  appreciably  increased  in  cases  in 
which  the  reaction  against  the  infection  is  well  marked,  especially 
in  the  early  stages  of  the  illness.  A  decrease  in  fibrin  is  com- 
mon in  patients  with  pronounced  anemia  and  in  those  who 
readily  succumb  without  reaction  against  the  infection.   •  ^ 

Thus  far  the  serum  test  has  given  no  reliable  clinical  informa- 
tion in  this  class  of  diseases,  although  several  clinicians  of  the 
French  school  claim  occasionally  to  have  observed  typical  clump- 
ing of  streptococcus  bouillon  cultures  with  the  serum  of  patients 
suffering  from  streptococcus  infections,  such  as  streptococcus  in- 
fected wounds,  sepsis,  puerperal  fever,  and  erysipelas;  but  nega- 
tive results  were  obtained  in  testing  bouillon  cultures  of  the 
staphylococcus  with  the  serum  of  staphylococcus  septicemia. 
The  evidence  brought  forward  to  show  that  the  serum  of  patients 
suffering  from  colon  infections  clumps  cultures  of  the  colon 
bacillus  is  by  no  means  conclusive;  for  many  races  of  the  colon 
bacillus,  it  may  be  recalled,  clump  spontaneously  and  are  agglu- 
tinated by  normal  serum. 


526 


GENERAL  HEMATOLOGY. 


If  a  test-tube  containing  blood  scrum  of  a  patient  suffering 
from  pncumococcus  septicemia  is  inoculated  with  a  pure  culture 
of  the  pneumococcus,  it  will  be  found  that,  after  twenty-four 
hours'  incubation,  the  serum  still  remains  free  from  turbidity 
and  shows  simply  a  slight  sediment  composed  of  pneumococci' 
capsuleless  and  glued  together  in  tenacious  clumps  or  in  serpen- 
tine, trailing  designs.  Pneumococci  grown  in  normal  serum 
cloud  the  liquid,  and  develop  a  new  growth,  consisting  of  encap- 
sulated, isolated  organisms.  Favorable  results  have  been  reported 
by  several  Continental  writers  who  have  used  this  test  clinically, 
but  its  diagnostic  value  must  still  be  regarded  as  questionable. 
.  For  a  review  of  the  literature  of  serum  diagnosis  in  sepsis  and 
m  other  conditions  the  reader  should  consult  Rosenberger's  com- 
prehensive article.1 

Blood  cultures  in  sepsis  are  more  frequently 
Bacteriology,  sterile  than  productive,  but  negative  results 
neither  exclude  the  existence  of  a  septic  process 
nor  necessarily  indicate  a  favorable  prognosis.  On  the  other 
hand,  positive  results  are  often  of  the  greatest  value  in  the 
diagnosis  of  obscure  cases  of  sepsis,  in  which  the  clinical  mani- 
festations are  more  or  less  vague.  As  pointed  out  by  Welch,2 
blood  cultures  in  which  the  Staphylococcus  pyogenes  alius  is  dem- 
onstrated have  little  significance  in  the  prognosis  of  the  case, 
whereas  the  presence  in  the  blood  of  the  other  pyogenic  cocci 
is  a  sign  of  intense  infection. 

The  results  obtained  by  different  investigators  in  the  bacterio- 
logical examination  of  the  blood  in  septicemia  vary  within  wide 
limits,  these  variations  being  explained  partly  by  the  differences 
m  the  technical  methods  used  by  each  reporter  and  partly  per- 
haps by  the  nature  of  the  infection.  Petruschky3  obtained  17 
positive  results  in  the  examination  of  59  cases  of  sepsis,  strepto- 
cocci being  found  in  15  and  staphylococci  in  2  instances.  Sitt- 
man4  examined  53  cases  of  septicemia,  and  succeeded  in  iso- 
lating streptococci  in  4,  staphylococci  in  n,  and  pneumococci 
in  6.  Czerniewski5  in  37  cases  of  puerperal  sepsis  obtained 
positive  results  in  10,  pure  cultures  of  streptococci  being  found 
in  all  the  grave  infections.  Symes6  obtained  positive  cultures 
in  9  of  31  cases  of  sepsis,  the  staphylococcus,  the  streptococcus, 
the  pneumococcus,  and  the  Micrococcus  tetragenus  having  been  the 

1  Proc.  Path.  Soc.  of  Phila.,  1904,  vol.  vii,  p.  97. 

2  Dennis'  "System  of  Surgery,"  Philadelphia,  1895,  vol.  i,  p.  251. 

3  Zeitschr.  f.  Hyg.  u.  Infektionskr.,  1894,  vol.  xvii,  p.  59. 

4  Deutsch.  Arch.  f.  klin.  Med.,  1894,  vol.  liii,  p.  323. 

5  Arch.  f.  Gynakol.,  1888,  vol.  xxxiii,  p.  73. 

6  Brit.  Med.  Jour.,  1901,  vol.  ii,  p.  709. 


SKPTICKMIA    AND  PYEMIA. 


527 


organisms  identified.  Kiihnau's  investigations1  show  a  much 
lower  percentage  of  positive  findings  than  are  commonly  re- 
ported, for  this  author,  in  23  cases  of  septicopyemia,  obtained 
growths  in  only  3  instances,  while  but  a  single  positive  finding 
resulted  from  the  examinations  of  12  cases  of  ulcerative  endo- 
carditis. Krauss,2  who  has  had  a  very  large  experience  in  the 
bacteriology  of  the  blood  in  various  infectious  diseases,  re- 
ports 7  positive  results  in  a  series  of  22  cases  of  septicemia, 
ulcerative  endocarditis,  and  erysipelas.  White,3  in  18  severe 
cases  of  sepsis,  all  of  which  were  fatal,  obtained  positive 
findings  in  4:  the  Streptococcus  pyogenes  3  times,  and  the  Staphy- 
lococcus pyogenes  aureus  once.  Canon4  obtained  11  positive 
results  in  the  examination  of  17  cases  of  septicemia,  pyemia, 
and  osteomyelitis.  Hirschlaff5  obtained  the  streptococcus  or 
staphylococcus  7  times  in  cultures  made  from  8  cases  of  sepsis. 
James  and  Tuttle,6  in  6  severe  septic  infections,  succeeded  in 
finding  the  streptococcus  in  2  instances.  Brieger7  obtained 
uniformly  negative  findings  in  the  examination  of  6  cases  of 
puerperal  sepsis.  Similar  results  have  also  been  reported  by 
Neumann,8  who  obtained  negative  findings  in  blood  cultures 
from  5  cases  of  pyemia.  Grawitz9  cultured  pyogenic  cocci  only 
once  in  his  examination  of  7  cases  of  malignant  endocarditis. 

Consideration  of  these  figures,  together  with  the  statistics  of  a 
number  of  other  reporters  of  smaller  series  of  cases,  furnishes  a 
total  of  316  cases  of  sepsis  in  which  it  is  reasonable  to  presume 
that  the  bacteriological  examination  of  the  blood  has  been  made 
by  dependable  methods.  Of  these  316  cases,  positive  results 
were  obtained  in  107,  while  the  remaining  209  proved  negative — a 
percentage  of  33.8  for  the  former.  This  analysis,  however,  is  not 
to  be  regarded  as  equivalent  to  the  statement  that  bacteriological 
examination  of  the  blood  gives  positive  diagnostic  information  in 
one-third  of  all  cases,  for  the  results  of  a  single  reliable  observer, 
rather  than  the  aggregate  figures  of  several,  are  to  be  considered 
in  order  to  arrive  at  a  true  estimate  of  the  value  of  this  procedure. 

Anemia,  of  a  grade  proportionate  to  the  inten- 
Hemoglobin  sity  of  the  infection,  is  the  rule  in  septic  cases, 
and         regardless  of  the  specific  nature  of  the  infective 
Erythrocytes,  process.    In  very  acute  cases  the  diminution  of 
hemoglobin  and  erythrocytes  may  be  so  excessive 

1  Zeitschr.  f.  Hyg.  u.  Infektionskr.,  1897,  vol.  xxv,  p.  492. 

2  Zeitschr.  f.  Heilk.,  1896,  vol.  xvii,  p.  117. 

3  Jour.  Exper.  Med.,  1899,  vol.  iv,  p.  425. 

4  Deutsch.  Zeitschr.  f.  Chirurg.,  1893,  vol.  xxxvii,  p.  571. 

5  Deutsch.  med.  Wochenschr.,  1897,  vol.  xxiii,  p.  766. 

6  Loc.  cit.  7  Charite-Annal.,  1888,  vol.  xiii,  p.  198. 

8  Berlin,  klin.  Wochenschr.,  1888,  vol.  xxv,  p.  143. 

9  Charite-Annal.,  1894,  vol.  xix,  p.  154. 


528 


GENERAL  HEMATOLOGY. 


and  so  rapid  that  an  abrupt  downward  curve  in  the  erythrocyte 
line  of  the  blood  chart  may  be  detected  from  day  to  day,  even 
from  morning  until  night,  in  some  instances.  This  rapidly  de- 
veloping type  of  anemia  is  associated  especially  with  fulminant 
cases  of  puerperal  septicemia,  in  which  counts  of  less  than  1,000,- 
ooo  cells  per  c.mm.  have  been  frequently  reported.  In  a  case  of 
this  sort  the  writer  found  the  hemoglobin  reduced  to  20  per  cent, 
and  the  erythrocytes  to  730,000  per  c.mm. 

In  less  severe  cases  the  development  of  the  anemia  is  slower 
and  of  a  more  moderate  grade,  the  hemoglobin  being  reduced  to 
40  or  50  per  cent.,  and  the  erythrocytes  to  about  2,500,000  or 
3,500,000  per  c.mm. 

The  following  estimates  show  the  blood  changes  found  in  a 
case  of  puerperal  sepsis  during  a  period  of  four  months  : 


Hemoglobin       Erythrocytes  Leucocytes 

Date.                          Percentage.         per  c.mm.  per  c.mm. 

April  29,  1901  57  3,380,000  17,200 

May  16,  1901  52  3,390,000  14,200 

June    2,  1901  38  2,640,000  29,400 

9?  I9°I  22  2,000,000  33, 100 

12,1901  '.--  ..25  1,600,000  19,000 

"     l6>  I9°I  3°  1,850,000  16,800 

"     21,  I9°I  25  1,902,250  27,200 

27,  1901  35  2,339,000  19,200 

Juty    5>  I9°I  30  2,050,000  8,600 

22,1901  30  2,300,000  6,000 

Aug.    6,1901  35  3,150,000  15,000 

"    i5>  !901   39  3>787,ooo  10,500 

22,  1901  48  3,637,000  9,200 

25,  1901  52  3,899,000  9,000 


The  color  index  is  diminished  moderately,  but  not  excessively, 
save  in  an  occasional  instance;  it  averaged  0.85  for  the  series  on 
page  529.  Hemoglobinemia  is  found  in  occasional  instances  of 
grave  character.  Most  writers  lay  stress  on  the  excessively 
watery  condition  of  the  serum,  particularly  in  those  cases  in  which 
the  development  of  anemia  is  early,  marked,  and  rapid. 

Deformities  of  shape  and  size  and  atypical  staining  phenomena 
are  marked  in  relation  to  the  degree  of  the  anemia;  they  are 
rarely  conspicuous,  except  in  long-standing  cases.  The  same  re- 
marks apply  to  the  presence  of  nucleated  erythrocytes.  Granular 
basophilia  is  found  with  more  or  less  constancy  in  severe  cases. 


SEPTICEMIA  AND  PYEMIA. 


529 


In  79  hospital  cases  of  septicemia  and  pyemia  the  hemo- 
globin and  erythrocyte  values  were  as  follows : 

Hemoglobin  Number  Erythrocytes  Number 

Percentage.        of  Cases.  per  c.mm.  of  Cases. 

From  90-100           1  Above  5,000,000   4 

"    80-90  14  From  4,000,000-5,000,000  21 

"    70-80            9  "     3,000,000-4,000,000  29 

"    60-70  14  "     2,000,000-3,000,000  17 

"    50-60  13  "     1,000,000-2,000,000   7 

"    40-50  15  Below  1,000,000   1 

"    30-40   6 

"    20-30   6 

Below  20    1 

Average,     58.9  per  cent.    Average,     3,430,687  per  c.mm. 

Maximum,  92.0      "  Maximum,  5,970,000   "  " 

Minimum,  19.0      "-  Minimum,    730,000   "  " 

Leucocytosis  is  always  present  in  those  cases 
Leucocytes,  in  which  the  infection,  either  moderate  or  marked, 
occurs  in  a  patient  whose  powers  of  resistance  are 
sufficiently  strong  to  react  against  the  poison.  The  increase  in 
the  number  of  leucocytes  is  usually  moderate,  counts  of  from  15,000 
to  25,000  being  commonest.  In  trifling  infections,  not  sufficiently 
marked  to  produce  activity  of  the  leucocyte-forming  organs, 
and  in  lethal  cases,  in  which  the  system  is  overwhelmed  by  the 
toxins,  not  only  does  leucocytosis  fail  to  develop,  but  sometimes 
distinct  leucopenia  may  be  observed.  These  facts  render  the 
occurrence  of  leucocytosis  in  septicemia  an  inconstant  sign,  for 
it  is  no  uncommon  experience  to  examine  case  after  case  of  un- 
doubted sepsis  without  encountering  any  increase  in  the  leucocytes 
above  normal.  In  the  series  tabulated  below  frank  leucocytosis 
was  found  in  92  instances,  or  in  approximately  70  per  cent.,  while 
in  11  cases,  or  about  8  per  cent.,  there  was  distinct  leucopenia,  the 
count  in  one  being  only  2000  per  c.mm.  All  the  cases  not  showing 
leucocytosis  were  either  very  mild  or  very  severe  infections. 

The  increase  affects  chiefly  the  polynuclear  neutrophiles,  which 
are  both  relatively  and  absolutely  increased  at  the  expense  of  the 
mononuclear  forms.  Mast  cells  and  myelocytes  in  small  numbers, 
are  common.  In  a  profoundly  anemic  case  of  sepsis  Kline  1 
found  striking  eosinophilia — 40  per  cent ;  a  decided  diminution  of 
these  cells  is,  however,  the  common  finding.  In  all  forms  of 
sepsis,  and  especially  in  puerperal  fever,  the  iodin  reaction  occurs 

1  Centralbl.  f.  inn.  Med.,  1899,  vol.  xx,  p.  97. 

34 


53° 


GENERAL  HEMATOLOGY. 


with  great  constancy.  Iodophilia  is  a  more  dependable  sign  of 
sepsis  than  the  behavior  of  the  leucocytes,  since  it  is  present  in 
many  cases  so  toxic  as  to  stifle  leucocytosis. 

One  hundred  and  thirty-five  cases  in  which  leucocyte  counts 
were  made  showed  the  following  averages: 

Leucocytes  per  c.mm  Number  of  Cases. 

Above  40,000   1 

From  30,000-40,000 .   6 

"     20,000-30,000  14 

"     15,000-20,000  27 

"     10,000-15,000...  44 

"       5,000-10,000  32 

Below   5,000  11 

Average,  15,040  per  c.mm. 

Highest,  41,600  " 

Lowest,     2,000  "  " 


The  value  of  the  blood  examination  as  an  aid 
Diagnosis,  to  the  diagnosis  of  septic  conditions  must  be  re- 
garded as  more  or  less  uncertain.  In  cases  with 
clinical  manifestations  suggesting  at  once  enteric  fever,  malarial 
jever,  and  septicemia  the  presence  of  leucocytosis  is  highly  sugges- 
tive of  the  latter  condition,  for  in  typhoid  and  in  malaria  leucocy- 
tosis rarely  exists,  except  in  the  event  of  some  complication.  The 
early  development  of  a  rapidly  increasing  anemia  would  also  point 
to  sepsis  rather  than  to  typhoid  or  malaria,  for  in  the  latter  fevers 
the  anemia,  although  it  begins  early,  does  not  reach  a  high  grade 
until  comparatively  late  in  the  course  of  the  illness.  The  pres- 
ence of  a  positive  serum  reaction,  or  the  discovery  of  malarial 
parasites  in  the  blood,  will,  of  course,  at  once  determine  the 
diagnosis.  If  the  diagnosis  lies  between  sepsis  and  miliary  tuber- 
culosis, increase  in  the  number  of  leucocytes  points  to  the  former. 
The  iodin  reaction  may  be  present  in  all  the  conditions  noted 
above. 

In  cases  without  leucocytosis  but  with  marked  iodophilia  a  bad 
prognosis  is  justified,  for  the  reason  stated  above. 


SPOTTED  FEVER  OF  MONTANA. 


531 


LXVI.  SPOTTED  FEVER  OF  MONTANA. 

Ovoid  bodies,  presumably  hematozoa,  have 
Parasitology,  been  found  first  by  Wilson  and  Chowning 1  and 
later  by  Anderson2  and  by  Cobb 3  in  the  circulating 
blood  of  those  ill  with  the  disease  known  as  spotted  fever,  or  tick 
fever,  prevailing  in  the  Bitter  Root  Valley  in  Montana.   The  former 
investigators  have  labeled  their  discovery  the  Piroplasma  hominis. 

The  ovoid  bodies  in  question  remind  one  of  both  the  Texas 
fever  and  the  malarial  parasite,  though  they  differ  from  the 
former  in  being  larger  and  in  possessing  ameboid  motility,  and 
from  the  common  forms  of  the  latter  in  being  unpigmented.  In 
the  fresh  blood  three  forms  of  the  piroplasma,  each  ovoid  in 
shape,  were  found  within  the  erythrocytes:  a  small  non-motile 
form,  1  to  2  fx  in  length  by  1  p  in  width;  a  larger,  actively  ame- 
boid form,  3  to  5  fi  in  length  by  1  to  1.5  ju  in  width,  and  showing 
a  dark  granular  spot  at  one  end;  and  a  twin  form,  consisting  of 
two  pear-shaped  bpdies  lying  with  their  tapered  ends  approaching, 
and  bearing  a  granular  spot  at  each  end.  Extracellular  diplococci- 
like  forms,  0.5  to  1  ft  in  size,  and  not  endowed  with  motion,  were 
also  identified.  In  the  dry  film  the  bodies  are  stained  best  by 
one  of  the  basic  dyes,  such  as  methylene-blue  or  thionin.  The 
theory  is  tempting  that  the  infection  of  spotted  fever  is  conveyed 
by  a  variety  of  tick  known  as  the  Dermacentor  reticulatus. 

Moderate  anemia,  usually  with  a  low  color 
Hemoglobin  index,  is  the  rule.    The  hemoglobin  percentage 
and         may  fall  as  low  as  50  or  60,  but  the  erythrocyte 
Erythrocytes,  count  remains  at  about  4,000,000  cells  per  c.mm. 

The  effect  of  high  altitude  in  masking  an  ane- 
mia must,  however,  be  taken  into  consideration,  for  the  counts 
in  all  the  reported  cases  of  spotted  fever  were  made  at  an  eleva- 
tion of  3500  feet  above  the  sea-level.  No  structural  changes  in 
the  erythrocytes  have  been  noted. 

The  leucocytes  are  slightly  increased — to  12,- 
Leucocytes.  000  or  13,000  per  c.mm. — and  show,  differen- 
tially, nothing  abnormal  save,  perhaps,  a  mod- 
erate increase  in  the  large  lymphocytes  at  the  expense  of  the  small 
hyaline  cells. 

The  specificity  of  the  ameboid  bodies  found 
Diagnosis,    in  this  disease  seems  to  be  well  established,  and 
their  detection  in  the  blood  should  prove  a 

1  Jour.  Amer.  Med.  Assoc.,  1902,  vol.  xxxix,  p.  131. 

2  Amer.  Med.,  1903,  vol.  vi,  p.  506. 

3  Public  Health  Rep.,  1902,  vol.  xvii,  p.  1868. 


532 


GENERAL  HEMATOLOGY. 


means  of  excluding  malarial  and  enteric  fevers.  From  the  latter 
the  absence  of  a  serum  reaction  and  the  presence  of  a  moderate 
leucocyte  increase  are  additional  points  of  differentiation. 


LXVII.  SYPHILIS. 

Micrococci  (Hallin;  Martineau),  pleomorph- 
ic acteriology.  ous  bacilli  (van  Niessen),  cocci-bacilli  (Klebs), 
bacteria  resembling  the  Klebs-Loffler  organism 
(Joseph  and  Piorkowski),  and  spore-like  bodies  (Klotzsch; 
Lostorfer)  are  some  of  the  prominent  " organisms"  which,  during 
the  last  three  decades,  have  been  found  in  the  circulating  blood 
of  syphilitics  and  have  been  exploited  as  the  exciting  cause  of  the 
disease.  The  vogue  of  these  findings,  as  well  as  that  of  those 
relating  to  the  presence  of  a  syphilitic  organism  in  various  tissues, 
has  been  ephemeral.  Lustgarten's  bacillus,  regarded  by  many 
as  specific,  has  thus  far  resisted  artificial  cultivation.  De  Lisle 
and  Jullien,  in  1901,  claimed  to  have  cultured  a  bacillus  from  the 
blood  of  syphilitics,  and  to  this  microbe  they  ascribe  specific 
properties.  The  bacillus  in  question  is  said  to  occur  constantly  in 
the  blood  during  the  secondary  manifestations  of  the  infection, 
and  to  excite  indurated  ulcer,  adenitis,  and  other  luetic  signs  when 
inoculated  into  animals.  It  possesses  peculiar  cultural  traits, 
for  an  account  of  which  the  reader  is  referred  to  De  Lisle's 
original  article.1 

During  the  early  stages  of  the  infection,  in  the 
Hemoglobin  interval  between  the  appearance  of  the  initial 
and  lesion  and  the  development  of  secondary  symp- 
Erythrocytes.  toms,  the  blood  changes  closely  counterfeit  those 
of  typical  chlorosis,  a  fact  which  has  led  to  the 
use  of  the  term  "syphilitic  chlorosis"  to  describe  the  blood  picture 
of  early  lues.  The  hemoglobin  progressively  falls  until  the  loss 
approximates  20  or  30  per  cent.,  while  the  number  of  erythrocytes 
remains  normal  or  is  but  slightly  diminished,  in  consequence  of 
which  the  color  index  is  low.  As  secondary  symptoms  appear 
oligocythemia  usually  develops,  and  in  some  instances  reaches 
a  high  grade.  There  is  a  close  relationship  between  the  intensity 
of  the  infection  and  the  intensity  of  the  anemia.  In  the  tertiary 
and  hereditary  forms  of  the  disease  if  treatment  is  neglected, 
the  count  may  fall  to  approximately  1,000,000  cells,  and  the  hemo- 
globin to  20  per  cent,  or  even  less,  while  extreme  poikilocytosis, 
megalocytosis,  and  microcytosis  may  be  present,  together  with 

1  Amer.  Med.,  1903,  vol.  vi,  p.  474. 


SYPHILIS. 


533 


numerous  normoblasts  and,  perhaps,  a  few  megaloblasts— 
the  so-called  "  syphilitic  pernicious  anemia."  But  the  anemia 
seldom  reaches  this  grade,  since  most  syphilitics  receive  adequate 
treatment  early  in  the  course  of  the  disease.  Lowenbach  and 
Oppenheim,1  from  a  recent  study  of  36  cases,  have  shown  that  a 
diminution  of  the  hemoglobin  and  iron  content,  with  trifling 
oligocythemia,  is  the  usual  finding  in  the  tertiary  stage. 

After  the  administration  of  mercury  both  the  hemoglobin  and 
the  erythrocytes  begin  to  increase,  the  former  more  slowly  than  the 
latter,  until  treatment  has  been  continued  for  about  two  or  three 
weeks,  but  should  this  drug  be  given  for  longer  than  this  period, 
just  the  opposite  effect  is  produced— first  a  diminution  in  the 
hemoglobin  percentage,  followed  later  by  oligocythemia.  Ossen- 
dowski 2  found  that  the  initial  increase  is  more  rapid  after  in- 
tramuscular injections  of  mercury  than  after  its  administration 
by  inunction  or  by  the  mouth.  He  also  determined  that  the  effects 
of  potassium  iodid  as  a  regenerator  of  the  hemoglobin  content 
are  more  decided  than  those  of  mercurials. 

BurTa3  concludes,  from  a  study  of  21  cases,  that  the  hemogenesis 
excited  by  mercury  is  temporary,  owing  chiefly  to  the  feeble 
resistance  of  the  newly  bred  cells,  many  of  which  perish  prema- 
turely. The  ultimate  effect  of  this  drug,  therefore,  is  hemolytic, 
although  it  may  antidote  the  poison  of  the  disease.  Extreme 
hemoglobin  loss  in  patients  undergoing  mercurialization  is  re- 
garded as  prognostic  of  severe  tertiary  manifestations  as  the  in- 
fection matures.  The  intravenous  injection  of  mercuric  chlorid 
rapidly  causes  hemoglobinemia  in  syphilitics.  It  is  a  well- 
recognized  clinical  fact  that  the  blood  changes  provoked  by 
syphilis  are  likely  to  be  more  marked  in  women  than  in  men, 
other  things  being  equal. 

Justus'  Test— This  reaction,  described  by  Justus,4  depends 
upon  the  presumption  that  in  untreated  cases  of  congenital, 
secondary,  and  tertiary  syphilis,  a  single  dose  of  mercury,  ad- 
ministered either  by  inunction  or  by  subcutaneous  or  intravenous 
injection,  causes  a  hemoglobin  loss  of  from  10  to  20  per  cent,  within 
about  twenty-four  hours,  this  abrupt  decline  being  followed 
within  a  few  days  by  a  rise  in  the  hemoglobin  value  to  a  some- 
what higher  figure  than  that  first  observed  before  the  drug  was 
given.  In  Justus'  last  communication,5  relating  to  over  500  cases, 
data  are  given  which  show  that  the  test  is  positive  in  from  70  to  80 

1  Deutsch.  Arch.  f.  klin.  Med.,  1903,  vol.  lxxv,  p.  22. 

2  Inaug.  Dissert.,  Dorpat,  1903.  3  Sem.  med.,  1903,  vol.  xxiii,  p.  75. 

4  Virchow's  Arch.,  1894,  vol.  cxl,  pp.  91  and  533. 

5  Deutsch.  Arch.  f.  klin.  Med.,  1903,  vol.  lxxv,  p.  1. 


534 


GENERAL  HEMATOLOGY. 


per  cent,  of  all  cases  of  florid  syphilis,  and  that  it  disappears  with 
the  involution  of  the  specific  lesions  and  reappears  with  their  recur- 
rence. It  is  further  claimed  that  negative  findings  are  constant  in 
healthy  persons  and  in  those  suffering  from  non-syphilitic  diseases. 
Failures  to  obtain  good  results  Justus  attributes  to  faulty  diagnosis 
and  to  wrong  technic— at  least  3  gm.  of  blue  ointment  for  an  adult 
or  1  gm.  for  a  child  must  be  used  for  the  inunction,  the  final  hemo- 
globin estimate  being  made  the  following  morning.  Cabot  and 
Mertins 1  obtained  positive  results  in  7  syphilitics,  and  also  in  one 
case  of  chlorosis  and  in  one  of  tertian  malarial  fever,  but  in  their 
hands  the  test  proved  negative  in  32  control  cases  of  other  diseases. 
Regarding  the  exceptional  non-syphilitic  diseases  in  which  the 
reaction  may  prove  positive,  Brown  and  Dale2  state  that  such 
cases  are  characterized  by  striking  oligochromemia.  A  thor- 
ough study  of  , the  test  has  been  made  by  Jones,3  who  examined 
53  cases,  of  which  number  35  were  syphilis,  and  18  cases  of  other 
diseases.  Of  the  former,  17  were  active  syphilis  untreated,  and  of 
these  the  test  was  positive  in  13  and  negative  in  4;  15  cases  of 
chancre  yielded  but  7  positive  results,  these  occurring  most  fre- 
quently in  chancre  with  adenitis;  in  two  cases  of  latent  syphilis  and 
in  one  of  active  syphilis  under  treatment  the  test  failed.  Tucker,4 
Huger,5  Christian  and  Foerster,6  and  Oppenheimer  and  Lowen- 
bach7  have  also  reported  similar  inaccuracies  in  the  test.  From 
the  statistics  of  these  investigators  (121  cases)  Ewing's  analysis8 
credits  the  test  with  positive  findings  in  62  per  cent,  of  cases  of 
active  syphilis,  in  30  per  cent,  of  chancre,  and  in  67  per  cent,  of 
chancroid.  In  the  writer's  experience,  limited  to  9  cases,  the 
success  of  the  test  has  been  uniform. 

The  diagnostic  value  of  Justus'  test  is  greatly  restricted  by  its 
frequent  failure  in  early  initial  lesions  and  in  latent  syphilis,  and 
its  occasional  failure  in  the  early  part  of  the  secondary  stage, 
periods  when  a  pathognomonic  test  would  prove  of  the  greatest 
aid.  The  fact  that  positive  reactions  may  occur  in  non-syphilitic 
diseases,  in  which  hypersensitiveness  to  the  action  of  mercury 
is  to  be  presumed,  obviously  is  against  the  test's  specificity. 

The  number  of  leucocytes,  which  remains  ap- 
Leucocytes.  proximately  normal  during  the  preemptive  stage 
of  the  disease,  usually  increases  moderately  with 

1  Boston  Med.  and  Surg.  Jour.,  1899,  vol.  cxl,  p.  323. 

2  Cincinnati  Lancet-Clinic,  1900,  vol.  xliv,  p.  261. 

3  N.  Y.  Med.  Jour.,  1900,  vol.  lxxi,  p.  513. 

4  Phila.  Med.  Jour.,  1902,  vol.  ix,  p.  846. 

5  Ibid.,  p.  849.  6  Univ.  Med.  Mag.,  1900,  vol.  xiii,  p.  634. 

7  Deutsch.  Arch.  f.  klin.  Med.,  1901,  vol.  lxxi,  p.  425. 

8  "  Clinical  Pathology  of  the  Blood,"  2d  ed.,  New  York  and  Philadelphia 
I9°3>  P-  342. 


TONSILLITIS. 


535 


the  appearance  of  the  secondary  symptoms.  Their  total  number 
rarely  equals  twice  the  maximum  normal  standard,  and  the  gain 
is  due,  in  the  great  majority  of  instances,  to  an  increase  in  the 
non-granular  hyaline  forms,  the  percentage  of  polynuclear  neutro- 
philes  being  relatively  low.  Many  authors  maintain  that  the 
eosinophils  are  increased,  but  Peter,1  who  has  especially  investi- 
gated this  question,  emphatically  states  that  in  no  form  and  at  no 
stao-e  of  syphilis  has  he  observed  eosinophilia.  In  the  leucocyte 
increase  frequently  found  in  the  high-grade  anemia  of  tertiary 
syphilis  the  lymphocytosis  is  especially  striking,  and  the  presence 
of  small  numbers  of  myelocytes  is  common.  Under  the  influence 
of  mercurial  or  iodid  treatment  the  leucocyte  count  diminishes, 
the  lymphocytes  decrease,  and  the  polynuclear  neutrophiles  grow 
more  numerous. 

The  writer  has  found  iodophilia  in  severe  syphilitic  anemia. 
In  patients  whose  blood  is  approximately  normal  no  numerical 
changes  in  the  blood  plaques  occur.    In  severe  syphilitic  anemia 
the  plaques  are  increased— a  change  for  which  Vomer2  blames 
the  anemia,  not  the  syphilis. 

But  slight  diagnostic  value  can  be  attached  to 
Diagnosis,  the  changes  in  the  blood  in  this  disease.  The 
association  of  a  low  color  index  and  a  leucocyte 
increase  chiefly  of  the  lymphocytes  is  suggestive,  but  nothing 
more.  Justus'  test,  if  positive,  strengthens  the  pertinence  of  the 
preceding  signs,  provided  that  all  sources  of  fallacy  can  be  ex- 
cluded; absence  of  the  reaction  by  no  means  excludes  syphilis. 
The  distinctions  between  tertiary  syphilitic  anemia  and  true  per- 
nicious anemia  have  already  been  discussed.    (See  p.  289.) 


LXVIII.  TETANUS. 

In  a  fatal  case  treated  with  antitoxin  Cabot3  found  70  per 
cent,  of  hemoglobin  and  11,900  leucocytes  per  c.mm.,  with  no  de- 
crease in  the  number  of  eosinophiles,  as  is  usual  in  most  febrile 
states.  In  two  other  cases,  also  fatal  and  treated  with  antitoxin, 
he  found  leucocytoses  of  19,600  and  18,200,  respectively. 


LXIX.  TONSILLITIS. 
As  a  general  rule,  no  appreciable  changes  are  found  in  the 
hemoglobin  and  erythrocytes,  although  in  severe  cases  the  former 
is  sometimes  diminished.    Leucocytosis  of  a  moderate  grade  may 
or  may  not  develop,  depending  largely  upon  the  character  of  the 

1  Dermatolog.  Zeitschr.,  1897,  vol.  iv,  p.  669. 

2  Deutsch.  med.  Wochenschr.,  1902,  vol.  xxviii,  p.  897.  Loc.  cit. 


536 


GENERAL  HEMATOLOGY. 


tonsillar  inflammation.  When  present,  the  increase  involves  prin- 
cipally the  polynuclear  neutrophils,  and  the  total  leucocyte  count 
rarely  exceeds  15,000  cells  to  the  c.mm.  Leucocytosis  is  less 
common  and  less  decided  in  follicular  tonsillitis  than  in  quinsy. 
In  the  latter  Pee,1  Rieder,2  and  others  have  observed  counts  in 
excess  of  20,000. 

The  leucocyte  count  is  of  no  aid  in  differentiating  tonsillitis, 
diphtheria,  and  streptococcus  inflammations  of  the  throat. 


LXX.  TRICHINTASIS.  • 

It  is  generally  agreed  that  there  are  no  changes 
Hemoglobin  in  the  hemoglobin  and  erythrocytes  attributable 
and         to  the  influence  of  this  infection,  high  counts  and 
Erythrocytes,  hemoglobin  estimates,  often  polycythemia,  being 
'  the  rule.    Rarely,  well-marked  anemia  may  be 
found,  due  to  some  other  cause,  as  in  a  case  reported  by  Kerr,3  in 
which  the  erythrocytes  numbered  between  3,300,000  and  3,340,- 
000  per  c.mm. 

T.  R.  Brown4  first  made  the  important  an- 
Leucocytes.  nouncement  that  acute  cases  of  trichiniasis  are 
accompanied  by  a  well-marked  increase  in  the 
number  of  leucocytes,  characterized  by  an  absolute  and  relative 
gain  in  the  eosinophiles.  This  observation  has  since  been  corrob- 
orated by  a  number  of  other  workers  whose  results  are  tabulated 
below. 

^  Unfortunately,  eosinophilia  cannot  be  regarded  as  constant  in 
this  condition,  as  shown  by  the  following  count  made  by  the  writer 
in  a  typical  case  of  trichiniasis  occurring  in  J.  Chalmers  Da  Costa's 
surgical  service  at  St.  Joseph's  Hospital: 

Hemoglobin  80  per  cent. 

Erythrocytes  4,400,000  per  c.mm 

Leucocytes   12,000  "  " 

Small  lymphocytes  36.7  per  cent. 

Large  lymphocytes  and  transitional  forms  ...  6.5 

Polynuclear  neutrophils  56.1 

Eosinophiles   0.5 

Myelocytes  „   0.2 

Basophiles   0.0 

Repeated  examinations  by  others  showed  practically  these 
figures,  the  eosinophiles  at  no  time  being  increased.    The  lesions 

1  Inaug.  Dissert.,  Berlin,  1890.  2  Loc^  ciL 

3  Phila.  Med.  Jour.,  1900,  vol.  vi,  p.  346. 

4  Johns  Hopkins  Hosp.  Bull.,  1897,  vol.  in,  p.  79;  also  Jour.  Exper.  Med.,  189S, 
vol.  iii,  p.  315- 


TRICHINIASIS. 


537 


in  this  patient  were  most  striking,  as  they  involved  the  greater 
part  of  the  right  lower  extremity,  from  calf  to  thigh.  Excised 
bits  of  muscles  from  the  affected  parts  were  found  to  be  swarm- 
ing with  trichinae  and  rich  in  eosinophile  cells.  It  is  possible 
that  in  such  instances  as  this  the  absence  of  eosinophilia  may  be 
attributed  to  the  overwhelming  nature  of  the  toxins,  which,  by 
their  repellant  action,  stifle  eosinophile  proliferation  in  the  marrow. 
This,  indeed,  has  been  proved  by  Opie,1  who  found  that  in  dogs 
mortally  infected  with  trichinae  the  circulatory  eosinophiles 
rapidly  diminished,  and  at  the  same  time  those  of  the  marrow, 
mesenteric  glands,  and  intestinal  mucosa  showed  marked  degenera- 
tive changes.  In  other  (milder)  cases,  as  the  disease  becomes 
chronic,  the  eosinophilia  of  the  early  stages  tends  to  disappear, 
as  is  the  rule  in  other  forms  of  helminthiasis.  Howard2  failed 
to  find  an  eosinophile  increase  in  a  single  case,  although  large 
numbers  of  these  cells  were  detected  in  the  muscle  lesions,  and 
Drake3  and  Schleip4  also  report  trichiniasis  without  eosinophilia. 

LEUCOCYTE  COUNT  AND  PERCENTAGE  OF  EOSINOPHILES  IN 
84  CASES  OF  TRICHINIASIS. 


Name  of  Reporter. 


T.R.Brown5  

Gwyn  6  

Kerr  7  

Blumer  and  Neuman 

Stump  9  

Cabot 10  

Atkinson  11  

Gordinier  12  

H.  Brooks  13  

Patek14  

Gould 15  

Cheney16  

Schleip 17  


1  Amer.  Jour.  Med.  Sci.,  1904,  vol.  cxxvi,  p.  477. 

2  Phila.  Med.  Jour.,  1899,  vol.  iv,  p.  1085. 

3  Jour.  Med.  Research,  1902,  vol.  hi,  p.  255. 

4  "Die  Homberger  Trichinosisepidemie  und  die  fur  Trichinosis  pathognomo- 
nische  Eosinophilic,"  Leipsic,  1904. 

5  Loc.  cit.      6  Centralbl.  f.  Bakt.  u.  Parasit.,  1899,  vol.  xxv,  p.  746.     7  Loc.  cit. 

8  Amer.  Jour.  Med.  Sci.,  1900,  vol.  cxix,  p.  14. 

9  Phila.  Med.  Jour.,  1899,  vol.  hi,  p.  1318. 

10  Boston  Med.  and  Surg.  Jour.,  1897,  vol.  cxxxvii,  p.  676;  also  "  Clinical  Ex- 
amination of  the  Blood,"  5th  ed.,  New  York,  1904. 

11  Phila.  Med.  Jour.,  1899,  vol.  hi,  p.  1243. 

12  Med.  News,  1900,  vol.  lxxvii,  p.  965.  13  Med.  Rec,  1900,  vol.  lviii,  p.  885. 
14  Amer.  Med.,  1901,  vol.  i,  p.  513.    '         15  Ibid.,  1903,  vol.  vi,  p.  515. 

16  Amer.  Med.,  1903,  vol.  vi,  p.  985.         17  Loc.  cit. 


Number 
of  Cases. 


Total  Number  of 
Leucocytes 
per  c.mm. 


8,000-35,000 
17,000 
10,000-25,000 
6,000-24,000 


1,410-25,000 
28,000 


18,000 


9,800 
12,000-15,000 
5,300-22,600 


Relative  Percentage 
of  Eosinophiles  to 
Other  Forms  of 
Leucocytes. 


8-O8.2 

33-65-9 
18.1-86.6 
8-50.4 
52 

7-8-37 
35-58.5 
3 1 -9-77 
15-83 
3° 

23  7-30.6 
10-17 
1.2-62.2. 


538 


GENERAL  HEMATOLOGY. 


The  other  differential  changes,  which  are  unimportant,  consist 
in  a  corresponding  relative  decrease  in  the  polynuclear  neutro- 
phils, and  occasionally,  in  the  early  stages  of  some  cases,  in  a 
similar  diminution  in  the  lymphocytes.  Mast  cells  and  myelocytes, 
in  small  numbers,  have  also  been  observed,  although  not  con- 
stantly. 

Blumer  and  Neuman's  studies  of  9  cases  of  epidemic  trichini- 
asis 1  lead  them  to  conclude  that  the  degree  of  leucocyte  increase 
corresponds  in  a  general  way  to  the  severity  of  the  attack,  rela- 
tively severe  cases  being  attended  with  a  higher  and  more  per- 
sistent increase  than  the  milder  attacks;  on  the  other  hand,  the 
intensity  of  the  infection  does  not  necessarily  correspond  to  the 
degree  of  eosinophilia.  The  latter  may  persist  for  months  after 
the  disappearance  of  the  leucocytosis  and  the  apparent  convales- 
cence of  the  patient,  but  just  how  long  it  does  last  is  as  yet  un- 
determined. 

The  presence  of  an  eosinophile  leucocytosis,. 
Diagnosis,  usually  of  a  high  grade,  may  be  the  only  indica- 
tion of  trichiniasis  in  obscure  cases  in  which  the 
characteristic  symptoms  of  the  infection  are  wanting,  and  in  such 
instances  the  change  is  to  be  regarded  as  a  most  valuable  aid  to 
diagnosis.  Absence  of  this  sign,  however,  does  not  definitely  ex- 
clude the  disease. 

LXXL  TRYPANOSOMIASIS. 

Nepveu,2  in  1898,  published  his  observations 
Parasitology,  on  finding,  eight  years  previously,  trypanosomata 
in  the  circulating  blood  of  man,  but  not  until  the 
discoveries  of  Forde,3  Dutton,4  Manson,5  and  Daniels6  were  pub- 
lished did  human  trypanosomiasis  become  recognized  as  a  dis- 
tinct entity  in  tropical  medicine.  To  Forde  and  to  Dutton  is 
due  the  credit  of  first  adequately  describing  the  organism. 
Since  the  pioneer  labors  of  these  investigators  our  knowledge 
of  the  condition  has  been  extended  by  the  studies  of  Castellani,7 
Bruce,8  Baker,9  Todd,10  Leishman,11  Nabarro,12  Sambon,13  Lave- 

1  Loc.  cit.  2  Compt.  rend.  Soc.  biol.,  Paris,  1898,  vol.  v,  p.  1172. 

3  Jour.  Trop.  Med.,  1902,  vol.  v,  p.  261. 

4  Brit.  Med.  Jour.,  1902,  vol.  ii,  p.  881;  1904,  vol.  ii,  p.  369;  also  Dutton  and 
Todd,  "First  Report  of  the  Trypanosomiasis  Expedition  to  the  Senegambia  (1902) 
of  the  Liverpool  School  of  Tropical  Medicine  and  Medical  Parasitology,"  Lancet, 
1903,  vol.  ii,  p.  1727. 

5  Brit.  Med.  Jour.,  1903,  vol.  i,  pp.  720  and  1249;  vol.  ii,  p.  645. 

6  Ibid.,  1903,  vol.  i,  p.  1249.  7  Ibid.,  1903,  vol.  i,  p.  143 1. 

8  Ibid.,  1903,  vol.  ii,  p.  1343.  9  Ibid.,  1903,  vol.  i,  p.  1254. 

10  Ibid.,  1903,  vol.  ii,  p.  645.  11  Ibid.,  1903,  vol.  i,  p.  1252. 

12  Lancet.,  1904,  vol.  i,  p.  229.  13  Ibid.,  1904,  vol.  i,  p.  228. 


TRYPANOSOMIASIS. 


539 


ran,1  and  others.  Aside  from  the  blood  findings,  human  trypano- 
somiasis is  characterized  by  progressive  asthenia,  wasting,  edema, 
splenic  tumor,  accelerated  pulse  and  respirations,  and  irregular 
fever  of  a  relapsing  type.  The  disease  runs  an  exceedingly 
chronic  course,  and  has'received  the  name  4 Trypanosoma  fever." 
Castellani2  was  the  first  to  demonstrate  the  presence  of  trypano- 
somata  in  the  blood  and  cerebrospinal  fluid  of  persons  suffering 
from  African  "sleeping  sickness,"  and  later  Bruce,3  having  con- 
firmed these  results,  repeated  the  original  suggestion  of  Maxwell 
Adams  that  many,  if  not  all,  of  the  cases  of  so-called  trypanosoma 
fever  in  reality  represent  early  stages  of  sleeping  sickness.  The 
presence  of  Castellani's  streptococcus,  and  of  Bettencourt's  diplo- 
streptococcus  (probably  the  same  organism)  in  the  cerebrospinal 
fluid  of  patients  infected  with  this  disease  is  thought  to  mean  a  con- 
comitant infection.  These  conclusions  have  recently  been  voiced 
by  the  Royal  Society's  Sleeping  Sickness  Commission.4  Singularly 
enough,  the  Portuguese  Commission,5  headed  by  Bettencourt, 
did  not  find  trypanosomata  in  sleeping  sickness,  which  they 
attribute  to  a  variety  of  streptococcus. 

There  is  possibly  a  relationship  (although  such  is  still  unproved) 
between  the  parasite  of  trypanosomiasis  and  certain  obscure  trop- 
ical maladies,  such  as  kala-azar,  dum-dum  fever,  tropical  spleno- 
megaly, and  the  undetermined  hyperpyrexias  of  West  Africa. 

The  organism  found  in  man,  tentatively  named  Trypanosoma 
gambiense,  is  regarded  as  a  form  of  trypanosoma  distinct  from  those 
responsible  for  tsetse-fly  disease,  surra,  dourain,  and  mal  de  cad- 
eras,  in  the  lower  animals.  The  parasites  multiply  by  fission,  but 
evidences  of  this  process  are  rarely,  if  ever,  found  in  the  circulating 
blood  of  the  periphery.  They  are  conveyed  by  a  species  of  tsetse- 
fly,  Glossina  palpalis,  which  acts  simply  as  a  mechanical  carrier 
of  the  parasite,  and  not  as  a  host  for  the  evolution  of  a  sexual 
cycle.  Laveran6  has  shown  that  the  administration  of  arsenic 
to  animals  infected  with  the  trypanosoma  causes  a  rapid  disap- 
pearance of  the  parasites  from  the  general  circulation,  and  it  has 
long  been  recognized  that  this  drug  has  a  favorable  action  in  the 
treatment  of  trypanosoma  disease  in  the  lower  animals.  Ehrlich 

1  Compt.  rend.  Acad.  d.  sc.,  Paris,  1904,  vol.  cxxxviii,  p.  841. 

2  Brit.  Med.  Jour.,  1903,  vol.  i,  pp.  1218  and  I431- 

3  /fo'd.,1903,  vol.  ii,  pp.  1008  and  1291;  1904,  vol.  ii,  p.  367.  _  _ 

4  Bruce,  Nabarro,  and  Greig,  "Report  of  the  Sleeping  Sickness  Commission 
of  the  Royal  Society  of  London,"  Brit.  Med.  Jour.,  1903,  vol.  11,  p.  1343;  .alsc> 
Dutton,  Todd,  and  Christy,  "First  Progress  Report  of  the  Expedition  of  the  Liver- 
pool School  of  Tropical  Medicine  and  Medical  Parasitology  to  the  Congo,  1903, 
ibid.,  1904,  vol.  i,  p.  186;  ibid.,  1904,  vol.  ii,  p.  369.  _ 

5  "  Doenga  do  Somno,"  Lisbon,  1902.         6  Sem.  med.,  1904,  vol.  xxiv,  p.  5«. 


54o 


GENERAL  HEMATOLOGY. 


and  Shiga1  effected  permanent  cures  in  trypanosomatous  mice  by 
the  use  of  trypan  red  (a  dye  belonging  to  the  benzopurpurin  series), 
given  hypodermically  and  by  the  mouth.  They  also  succeeded  in 
establishing,  by  the  use  of  this  drug,  a  transient  immunity  against 
the  infection. 

In  the  fresh  specimen  of  blood  the  parasite  appears  as  a  minute, 
worm-like  organism  which  glides  about,  with  undulatory  motility, 
between  the  collections  of  blood  corpuscles  (Fig.  64).  It  is 
readily  recognized  as  a  flagellated  protozoon,  one  end  of  which 
is  bluntly  conical,  and  the  other  drawn  out  into  a  whip-like 
flagellum  (rarely  two  flagella  occur),  while  a  transparent,  flange- 
like process  or  undulatory  membrane  is  attached  along  one  side 


Fig.  64. — Trypanosoma  Gambiense. 
From  a  stained  specimen  furnished  by  Dr.  J.  E.  Dutton. 


of  the  body.  The  latter  is  a  rather  short,  granular  structure, 
provided  with  a  highly  refractile  spot,  or  nucleus,  near  the  blunt 
end.  The  movements  of  the  worm,  both  forward  and  backward, 
are  effected  by  a  sort  of  screw-like  motility,  beginning  in  the  flagel- 
lated process  and  shared  by  the  undulatory  membrane  and  by  the 
body  protoplasm.  In  the  fresh  specimen  the  trypanosomata  perish 
within  from  one  to  three  hours  after  the  blood  is  drawn.  In  the 
stained  film  Dutton2  found  that  the  parasites  measured  from  18 
to  25//  in  length  and  from  2  to  2.8  fx  in  width,  and  that  they 
bear,  just  posterior  to  the  nucleus,  a  centrosome  or  micronucleus. 
With  Wright's  or  Irishman's  polychrome  methylene-blue  stains 

1  Berlin,  klin.  Wochenschr.,  1904,  vol.  xli,  pp.  329  and  362.  2  Loc.  cit. 


TUBERCULOSIS. 


54i 


the  protoplasm  is  colored  pale  blue,  and  the  nucleus,  centrosome, 
and  flagellum  red.  The  organisms  stain  better  with  carbolfuchsin 
than  wfth  the  weaker  basic  dyes,  such  as  hematoxylin. 

In  the  cases  of  trypanosomiasis  thus  far 
Hemoglobin  studied  there  has  been  found  well-defined,  al- 
and         though  not  excessive,  anemia.    In  no  instance 
Erythrocytes,  has  the  hemoglobin  fallen  below  36  per  cent., 
nor  the  erythrocytes  below  2,825,000  per  c.mm., 
and  in  most  cases  the  loss  amounted  to  about  20  or  25  per  cent., 
affecting  both  elements  proportionately.    The  erythrocytes  deviate 
but  little  from  their  normal  size  and  shape,  and  normoblasts  (found 
only  occasionally,  in  small  numbers)  are  the  only  form  of  nucleated 
erythrocytes  encountered. 

The  leucocyte  counts,  absolute  and  differential, 
Leucocytes,  are '  not  unlike  those  of  the  malarial  fevers, 
showing  either  a  normal  or  a  subnormal  total  es- 
timate and  a  decided  relative  lymphocytosis  affecting  the  large 
lymphocytes.  These  cells  are  increased  to  twice  or  thrice  their 
normal  percentage,  at  the  expense  of  the  polynuclear  neutrophiles, 
without  appreciable  alteration  in  the  proportion  of  small  lympho- 
cytes and  eosinophiles.  Mast  cells  (J  to  \  per  cent.),  as  well  as 
indeterminate  hyaline  cells,  resembling  those  found  in  myelogenous 
leukemia,  were  also  noted  in  the  cases  examined  by  Duncan, 
Daniels,  and  Low.1  Daniels2  pictures  these  cells  as  having  a 
relatively  large  nucleus,  staining,  by  the  Romanowsky  method,  a 
delicate  pink  splotched  with  purple,  encircled  by  a  narrow  zone 
of  blue  non-granular  protoplasm. 

The  detection  of  trypanosomata  in  the  blood 
Diagnosis,    is  obviously  the  key  to  the  diagnosis,  but  in  cases 
in  which  no  organisms  can  be  found,  a  well- 
defined  anemia  with  a  low  leucocyte  count,  characterized  by  an 
excess  of  large  lymphoid  cells  and  by  moderate  basophilia,  gives 
a  very  suggestive  blood  picture. 

LXXII.  TUBERCULOSIS. 
A  pure  infection  with  Koch's  bacillus  of  tuber- 
General     culosis  is  capable  of  producing  comparatively 
Features,     slight  alteration  in  the  composition  of  the  blood, 
such  changes  as  may  be  associated  with  tuber- 
culous processes,  whatever  organs  they  involve,  being  due  chiefly 
to  secondary  infection  with  other  bacteria,  usually  of  pyogenic 

1  Cited  by  Manson  and  Daniels,  Brit.  Med.  Jour.,  1903,  vol.  i,  p.  1249. 

2  "Studies  in  Laboratory  Work,"  London,  1903,  p.  68. 


542 


GENERAL  HEMATOLOGY. 


type,  and  not  to  the  disease  per  se.  The  prolonged  ill  effects  of 
tuberculosis  upon  body  nutrition  must  also  in  time  cause  more 
or  less  blood  impoverishment,  but  it  is  a  well-recognized  clinical 
fact  that  the  changes  are,  as  a  rule,  trivial  in  comparison  with  the 
gravity  of  the  disease  and  the  apparent  degree  of  cachexia.  The 
above  facts  are  sufficient  to  explain  the  reason  for  the  varied 
blood  pictures  found  in  tuberculosis—pictures  ranging  from  those 
of  practically  normal  blood  to  those  of  most  intense  anemia,  and 
from  leucopenia  to  frank  leucocytosis. 

In  a  limited  number  of  cases  of  acute  miliary 
Bacteriology,  tuberculosis  the  specific  bacillus  has  been  isolated 
from  the  blood  during  life  by  culturing  and  by 
intraperitoneal  inoculation  in  animals;  but  in  this  as  well  as  in 
the  other  forms  of  the  disease  this  procedure  generally  results  nega- 
tively so  far  as;  the  detection  of  the  tubercle  bacillus' is  concerned. 
Nattan-Larrier's  method1  of  examining  fluids  for  tubercle  bacilli 
is  worthy  of  trial.  An  injection  of  2  or  3  c.c.  of  blood  is  made  into 
a  guinea-pig's  mammary  gland,  in  which  the  organisms  rapidly 
multiply.  A  sample  of  milk  expressed  from  the  inoculated  gland 
is  examined,  after  the  lapse  of  a  few  days,  by  the  technic  used  in 
sputum  staining,  with  the  result  that  in  positive  cases  tubercle 
bacilli  are  found,  generally  within  from  five  to  ten  days  after  the 
injection.  In  advanced  septic  cases  of  pulmonary  tuberculosis, 
streptococci,  staphylococci,  blastomycetes,  and  other  micro-organ- 
isms have  been  found  in  the  blood,  but  only  rarely,  for  the  septic 
process  tends  to  remain  localized  in  the  lungs,  rather  than  to  in- 
vade the  general  circulation. 

Serum  Test. — Arloing  and  Courmont2  have  succeeded  in  pre- 
paring cultures  with  which  they  claim  that  the  serum  diagnosis 
of  tuberculosis  can  be  carried  out.  Glycerin  peptone  bouil- 
lon, inoculated  with  an  old,  attenuated  culture  of  the  tubercle 
bacillus  and  thoroughly  agitated  each  day  to  insure  homoge- 
neity of  the  culture,  finally  develops  a  growth  in  which  the  bacilli 
are  uniformly  disseminated  and  actively  motile.  Blood  serum 
from  the  suspected  case  is  mixed  in  small  test-tubes  with  the 
culture  thus  prepared,  in  proportions  of  1  to  5,  1  to  10,  and  1  to  20, 
and  the  tubes  inclined  at  an  angle  of  45  degrees,  being  examined 
at  intervals  of  two,  ten,  and  twenty-four  hours.  A  positive  reaction 
is  indicated  by  a  clarification  of  the  mixture  and  the  deposition 
of  small  flakes  or  granules  in  the  bottom  of  the  tube,  while  microscop- 
ically it  may  be  seen  that  the  bacilli  are  clumped  and  motionless. 
With  this  technic,  reactions  occurring  after  the  lapse  of  twenty- 

1  Presse  med.,  1903,  vol.  ii,  p.  838. 

2  Congres  pour  FEtude  de  la  Tuberculose,  1898. 


TUBERCULOSIS.  543 


four  hours  arc  without  clinical  significance.  Or  Koch's  method  of 
using  a  solution  of  sterile  " tubercle  powder"  may  be  employed. 
A  test  solution  is  made  by  dissolving  pulverized  sterile  tubercle 
cultures  in  normal  salt  solution,  and  then  centrifugalizing  the 
fluid,  so  as  to  obtain  a  clear,  opalescent  liquid  free  from  bacilli. 
The  test  fluid  thus  prepared  is  mixed  with  the  suspected  blood 
serum,  sedimentation  occurring  after  twenty-four  hours  in  positive 
reactions.  With  normal  serum  in  a  dilution  of  i  to  5  positive  re- 
actions do  not  occur,  and  they  occur  but  rarely  with  tuberculous 
serum  in  a  dilution  higher  than  1  to  20.  A  peculiarity  about 
this  test  is  that  it  takes  place  in  an  inverse  ratio  to  the  intensity 
of  the  infection,  and  hence  it  fails  in  advanced  and  virulent  cases  m 
which  presumably  there  is  already  an  excessive  auto-intoxication 
with  tuberculin.  Excluding  such  cases,  Arloing  and  Courmont 
found  that  positive  reactions  were  constant  in  all  tuberculous 
patients,  but,  unfortunately,  they  also  found  similar  results  in 
some  normal  individuals  and  in  various  non-tuberculous  diseases. 

Bendix2  found  the  test  successful  in  34  of  36  cases  of  tubercu- 
losis, the  two  failures  being  in  instances  of  overwhelming  infections ; 
he  also  claims  that  normal  blood  and  the  blood  from  other  dis- 
eases give  negative  results.  Nine  cases  of  pulmonary  tubercu- 
losis, 4  of  pleurisy,  and  17  of  various  non-tuberculous  affections 
were  examined  by  Mongour  and  Buard.3  All  the  phthisis  cases 
and  3  of  the  4  pleurisies,  which  were  tuberculous,  were  positive, 
the  case  not  reacting  proving  to  be  non-tuberculous.  In  15  of  17 
other  diseases  the  results  of  the  test  corresponded  with  the  clinical 
diagnosis  and  the  autopsy  findings.  Similar  results  in  tuberculous 
pleurisy  were  obtained  by  P.  Courmont,4  who  found  positive 
reactions  in  10  of  n  cases  clinically  tuberculous,  while  of  9  cases 
clinically  non-tuberculous  4  were  positive  and  5  negative.  In 
12  cases  of  ascites,  7  due  to  hepatic  cirrhosis  failed  to  react,  but 
the  other  5,  all  clinically  tuberculous,  gave  positive  results.  Re- 
sults distinctly  less  favorable  than  those  reported  by  other  in- 
vestigators are  published  by  Beck  and  Rabinowitch,5  but  it  is 
not  at  all  improbable  that  these  discrepancies  may  be  attributed, 
at  least  in  part,  to  the  use  of  unsuitable  cultures.  According 
to  these  authors'  experiments,  only  6  of  17  cases  of  incipient 
lung  tuberculosis  were  positive,  and  but  4  of  16  advanced  cases. 
Of  5  suspected  cases  that  reacted  to  tuberculin  injections,  but 
one  gave  a  positive  serum  reaction.    They  furthermore  found 

1  Deutsch.  med.  Wochenschr.,  1901,  vol.  xxvii,  p.  829. 

2  Ibid.,  1900,  vol.  xxvi,  p.  224. 

3Compt.  rend.  Soc.  biol,  Paris,  1898,  vol.  v,  p.  1142;  also  Buard,  Jour,  de 
phys.  et  path,  gen.,  1900,  vol.  ii,  p.  797. 

*  Congres  pour  l'Etude  de  la  Tuberculose,  1898. 

5  Deutsch.  med.  Wochenschr.,  1900,  vol.  xxvi,  p.  400. 


544 


GENERAL  HEMATOLOGY. 


that  positive  reactions  may  occur  in  healthy  persons,  and  in 
rheumatic  fever,  bronchitis,  hepatic  cirrhosis,  and  croupous  pneu- 
monia. Von  Gebhardt  and  Torday,1  using  Arloing's  homo- 
geneous cultures,  found  that  in  56  of  75  tuberculous  patients  and 
35  of  96  non-tuberculous  diseases  the  test  was  positive,  and  that 
a  similar  result  occurred  in  3  of  5  healthy  persons  examined. 
Rumpf  and  Guinard2  obtained  positive  results  in  90  of  107  cases. 
Kazarinoff,3  who  examined  73  tuberculous  and  10  normal  persons, 
found  the  test  uniformly  positive  in  the  former  and  negative  in  all 
the  latter  except  one.  Ivanov4  obtained  the  reaction  in  14  of  21 
cases  tested.  Romberg5  has  determined  that  the  serum  of  more 
than  50  per  cent,  of  persons  who  fail  to  show  clinical  evidences  of 
tuberculosis  possesses  a  more  or  less  agglutinative  property. 

The  serum  test  in  tuberculosis,  as  at  present  elaborated, 
must  be  considered  of  questionable  diagnostic  value,  since  it  has 
been  shown  that  it  may  occur  in  normal  individuals  and  in  non- 
tuberculous  diseases,  and  that  it  may  often  be  negative  in  affec- 
tions undoubtedly  tuberculous.  The  reaction  appears  to  be- 
come less  and  less  marked  as  the  disease  advances,  and  to  be 
more  striking  in  mild  than  in  severe  lesions.  Marchetti  and 
Stefanelli,6  for  example,  in  a  study  of  73  cases  of  pulmonary  and 
abdominal  tuberculosis,  found  that  88  per  cent,  of  early,  mild 
cases  and  but  42  per  cent,  of  late,  grave  cases  reacted  positively  to 
the  test.  Romberg,7  in  105  cases,  found  that  the  reaction  occurred 
in  80  per  cent,  of  cases  in  the  first  stage  of  phthisis,  in  66  per  cent, 
in  the  second  stage,  and  in  57  per  cent,  in  the  third  stage.  Wright8 
values  the  test  chiefly  as  an  index  to  the  organism's  ability  to 
elaborate  antibactericidal  substances,  as  shown  by  the  development 
of  the  reaction  in  the  blood  of  patients  subjected  to  therapeutic 
inoculations  of  tubercle  vaccine.  As  compared  with  Widal's  ty- 
phoid reaction,  the  test  of  Arloing  and  Courmont  is  crude  and 
untrustworthy. 

The  change  most  frequently  observed  is  a 
Hemoglobin  moderate  loss  of  hemoglobin,  with  little  or  no 
and         decrease  in  the  number  of  erythrocytes,  and  a 
Erythrocytes,  low  color  index,  resembling  somewhat  the  blood 
picture  of  chlorosis.    In  such  instances  poorly 
colored,  small-sized  corpuscles  may  be  numerous,  but  poikilocytes 
and  other  structural  alterations  in  the  cells  are  absent.    In  cases  in 

1  Munch,  med.  Wochenschr.,  1902,  vol.  xlix,  p.  1171. 

2  Deutsch.  med.  Wochenschr.,  1902,  vol.  xxviii,  p.  131. 

3  Jour.  Amer.  Med.  Assoc.,  1902,  vol.  xxxviii,  p.  362. 

4  Sem.  med.,  1902,  vol.  xxii,  p.  207. 

5  Deutsch.  med.  Wochenschr.,  1901,  vol.  xxvii,  p.  292. 

6  Riv.  Crit.  d.  Clin.  Med.  Fir.,  1903,  vol.  iv,  pp.  657,  673,  and  689. 

7  Munch,  med.  Wochenschr.,  1902,  vol.  xlix,  p.  89. 

8  Lancet,  1903,  vol.  i,  p.  1299. 


TUBERCULOSIS. 


545 


which  the  effects  of  a  complicating  septicemic  process  are  active 
the  above  changes  may  be  aggravated,  and  a  secondary  anemia  of 
variable  intensity  is  thus  developed.  The  oligocythemia  becomes 
marked  and  more  proportionate  to  the  oligochromemia,  the  color 
index  consequently  rising;  deformities  of  shape  and  size  and 
degenerative  stroma  changes  become  evident;  and  in  severe  cases 
an  occasional  normoblast  may  stray  into  the  circulation,  especially 
after  the  occurrence  of  a  hemorrhage.  But  these  qualitative 
changes,  even  in  advanced  cases  with  marked  cachexia,  are  com- 
paratively uncommon,  and,  when  present,  are  usually  not  striking 
in  spite  of  the  gravity  of  the  disease. 

Appelbaum1  points  out  that  in  a  group  of  phthisis  cases  char- 
acterized by  the  alar  chest,  by  underweight,  and  often  by  a  scrofu- 
lous history,  a  decided  anemia  is  likely  to  develop  long  before 
physical  and  bacteriological  signs  become  manifest.  Both  Baum- 
holtz2  and  Gozdzicki3  have  determined,  in  a  large  series  of  cases, 
that  the  resistance  of  the  erythrocytes  is  lowered  proportionately 
to  the  intensity  of  the  systemic  infection. 

Finally,  in  a  large  proportion  of  tuberculous  patients,  neither 
the  hemoglobin  nor  the  erythrocytes  fall  below  the  normal  stand- 
ard, this  being  the  rule  both  in  incipient  cases  and  in  those  which, 
although  of  greater  chronicity,  have  escaped  mixed  infection  or 
have  successfully  withstood  the  ill  effects  of  the  constitutional  drain. 
Incipient  cases  may  even  show  polycythemia  with  excessive  hemo- 
globin figures. 

In  25  hospital  cases  of  pulmonary  tuberculosis  in  various  stages 
the  writer  found  the  hemoglobin  percentage  from  20  to  30  in  1 ; 
from  30  to  40  in  4;  from  40  to  50  in  4;  from  50  to  60  in  5;  from 
60  to  70  in  4;  from  70  to  80  in  6;  and  from  80  to  90  in  1.  The 
lowest  estimate  was  20,  and  the  highest  83,  per  cent.  The  ery- 
throcytes were  in  excess  of  5,000,000  in  3  cases;  from  4,000,- 
000  to  5,000,000  in  10;  from  3,000,000  to  4,000,000  in  n,  and 
from  2,000,000  to  3,000,000  in  1.  The  minimum  count  was 
2,660,000,  and  the  maximum  5,500,000,  cells  per  c.mm.  M.  L. 
Stevens4  found  these  averages  in  100  cases  of  phthisis:  Males — 
hemoglobin,  76.7;  erythrocytes,  5,039,000;  color  index,  0.76; 
leucocytes,  14,060;  specific  gravity,  1.056.  Females — hemo- 
globin, 72;  erythrocytes,  4,373,000;  color  index,  0.73;  leucocytes, 
12,666;  specific  gravity,  1.054.  These  estimates  were  made  in 
Asheville,  at  an  altitude  of  2300  feet  above  sea-level,  and  there- 
fore are  doubtless  too  high  for  the  average  patient. 

1  Berlin,  klin.  Wochenschr.,  1901,  vol.  xxxix,  p.  7. 

2  Sem.  med.,  1900,  vol.  xx,  p.  319.  3  Ibid.,  1903,  vol.  xxiii,  p.  131. 
4  Med.  Rec,  1902,  vol.  lxii,  p.  133. 

35 


546 


GENERAL  HEMATOLOGY. 


From  a  study  of  43  cases  of  coxalgia,  vertebral  tuberculosis, 
and  tuberculous  osteomyelitis,  Dane 1  concludes  that  most  cases  of 
tuberculous  disease  of  the  bones  and  joints  do  not  cause  a  de- 
crease in  the  number  of  erythrocytes,  although  they  do,  however, 
affect  the  percentage  of  hemoglobin,  giving  rise  to  a  mild  degree 
of  "chloro-anemia,"  so-called.  An  analysis  of  his  series  shows 
that  the  hemoglobin  percentage  ranged  from  80  to  90  in  2  cases ; 
from  70  to  80  in  11 ;  from  60  to  70  in  24;  from  50  to  60  in  4;  and 
from  40  to  50  in  2.  The  erythrocytes  numbered  5,000,000  or 
more  in  24  cases,  ranging  between  6,000,000  and  7,000,000  plus 
in  6;  from  4,000,000  to  5,000,000  in  15;  from  3,000,000  to  4,000,000 
in  3;  and  from  2,000,000  to  3,000,000  in  1.  According  to  P.  K. 
Brown's  investigations  of  73  cases  of  bone  tuberculosis,2  the 
erythrocytes  decrease  only  in  long- continued  and  extensive  lesions 
occurring  in  young  children,  and  in  secondary  septic  infections,  while 
the  hemoglobin  is  diminished  practically  in  all  cases,  the  loss  de- 
pending upon  the  same  factors  which  influence  the  erythrocytes. 
He  also  observed  that  the  patient's  return  to  health  is  indicated  by 
a  tendency  of  the  blood  to  return  to  the  normal  standard.  In 
about  15  per  cent,  of  this  author's  cases  there  was  an  erythrocyte 
loss  of  1,000,000  or  more  cells  per  c.mm.,  and  in  all  but  some  half 
dozen  the  hemoglobin  was  diminished,  in  one  case  to  as  low  as  1 5 
per  cent. 

In  cases  with  secondary  septic  infection  the  anemia  disappears 
as  the  patient's  recuperative  powers  become  active,  but  should  the 
system  be  overwhelmed  by  the  intensity  of  the  pyogenic  process, 
the  anemia  either  remains  stationary  or  grows  more  marked. 

In  other  forms  of  the  disease — tuberculous  adenitis,  meningitis, 
pericarditis,  pleurisy,  peritonitis,  and  lesions  of  the  genito -urinary 
system— the  changes  affecting  the  erythrocytes  and  their  hemo- 
globin content  do  not  differ  from  those  already  described.  Well- 
developed  secondary  anemia  is  not  uncommon  in  the  two  last- 
named  forms  of  tuberculosis,  while  in  the  glandular  variety  dis- 
proportionately low  hemoglobin  values  are  frequently  found.  It 
is  to  be  recalled  that  apparent  polycythemia  may  be  encountered 
in  both  tuberculous  peritonitis  and  pleurisy,  due  in  the  former  in- 
stance to  the  inspissating  effect  of  the  purging  and  in  the  latter 
to  the  same  effect  produced  by  the  sudden  accumulation  of  an 
extensive  exudate. 

Much  the  same  factors  which  influence  the 
Leucocytes,  erythrocytes  also  determine  the  behavior  of  the 
leucocytes  in  the  different  forms  of  tuberculo- 

1  Boston  Med.  and  Surg.  Jour.,  1896,  vol.  cxxxiv,  pp.  529,  559,  and  589. 

2  Trans.  Med.  Soc.  of  State  of  California,  1897,  vol.  xxvii,  p.  168. 


* 

TUBERCULOSIS. 


547 


sis.  In  cases  of  unmixed  infection  these  cells  do  not  rise  above 
the  normal  limits  of  health,  but  the  moment  the  tuberculous 
lesion  becomes  complicated  by  a  secondary  infectious  process, 
such  as  a  septicemia,  the  accident  is  heralded  by  a  prompt  in- 
crease in  their  number.  For  example,  in  a  simple  tubercu- 
lous adenitis  the  count  is  normal,  but  should  the  glands  ulcer- 
ate, fistulate,  and  become  septic,  a  leucocytosis  at  once  develops. 
As  a  rule,  the  qualitative  changes  are  inconspicuous,  although 
in  some  forms  of  the  disease,  as  will  be  shown  below,  there 
is  a  tendency  toward  lymphocytosis.  Increase  in  the  number 
of  leucocytes,  characterized  by  a  relative  gain  in  the  lymphocytes 
and  eosinophiles,  usually  develops  during  the  reactionary  fever 
following  the  injection  of  tuberculin. 

The  theory  that  Neusser's  " perinuclear  basophilic  granules" 
are  a  favorable  prognostic  sign  in  tuberculosis  has  been  effectu- 
ally exploded,  since  later  research  has  proved  that  these  so-called 
granules  are  simply  artefacts.  (See  p.  228.)  Iodinophile  cells 
are  generally  found  in  septic  cases,  but  not  in  pure  tuberculosis. 

In  pulmonary  tuberculosis  leucocytosis  may  be  symptomatic 
of  cavities,  of  rapidly  spreading  bronchopneumonia,  and  of  acute 
pleurisy.  It  also  usually  follows  hemorrhage  of  any  considerable 
extent,  and  may  develop  as  the  effect  of  a  tuberculous  diarrhea. 
No  definite  relationship  apparently  exists  between  the  degree  of 
pyrexia  and  the  leucocyte  count.  Incipient  cases  of  simple  tu- 
berculous infiltration  and  pure  lung  cirrhosis  are  not  accompanied 
by  an  increase.  Of  the  25  cases  above  referred  to,  about  one- 
half  showed  a  moderate  leucocytosis,  in  12  the  count  being  10,000 
or  higher;  in  6  between  9000  and  10,000;  in  2  between  8000  and 
9000;  and  in  2  between  3000  and  8000  per  c.mm.  The  highest 
estimate  was  22,000,  and  the  lowest,  3152.  Differential  counts 
in  11  of  the  cases  having  an  increase  of  10,000  or  more  revealed 
no  qualitative  changes  other  than  those  typical  of  an  ordinary 
polynuclear  neutrophile  leucocytosis.  It  may  be  added  that  in  6 
of  these  11  counts  the  eosinophiles  were  entirely  absent.  Mye- 
locytes, in  fractions  of  one  per  cent.,  were  found  in  cases  with 
high-grade  anemia. 

Swan,1  from  a  careful  study  of  25  cases  of  phthisis,  concludes 
that  an  absence  of  eosinophiles  is  an  unfavorable  prognostic 
sign,  but  that  an  increase  of  these  cells  while  the  patient  is  under 
treatment  indicates  that  the  progress  of  the  disease  has  a  tendency 
to  become  arrested.  Pesel2  regards  basophilia  as  an  index  to 
the  progress  of  phthisis,  having  found  a  basophile  increase  in  cases 
improving  under  bettered  hygiene  and  a  diet  rich  in  nitrogen. 

1  Jour.  Amer.  Med.  Assoc.,  1904,  vol.  xlii,  p.  696. 

2  Med.  Press  and  Circular,  1903,  vol.  lxxvi,  p.  474 


548 


GENERAL  HEMATOLOGY. 


A.  M.  Holmes1  believes  that  it  is  possible  to  estimate  not  only 
the  degree  of  the  tuberculous  process,  but  the  degree  of  the  in- 
dividual's recuperative  powers,  by  a  careful  study  of  the  leuco- 
cytes, using  a  special  technic  of  staining  with  acid  and  basic 
dyes.  Briefly,  he  considers  that  the  pretuberculo.us  stage  is  char- 
acterized by  an  absence  of  leucocytosis,  a  slight  decrease  in  the 
lymphocytes,  little  or  no  increase  in  the  polynuclear  neutro- 
phils, more  or  less  abundant  debris  from  cell  disintegration,  and 
feeble  differentiating  powers  of  the  cells.  In  the  stage  of  early 
incipiency  he  finds  that  there  may  or  may  not  be  leucocytosis, 
accompanied  by  a  gain  in  the  polynuclear  neutrophils  at  the  ex- 
pense of  the  lymphocytes  as  the  disease  advances,  together  with 
well-marked  signs  of  cell  disintegration  and  impaired  differentia- 
tion. In  the  advanced  stage,  with  cavity  formation  and  extensive 
distribution  of,  the  lesions  through  the  lungs,  the  preceding  signs 
are  thought  to  be  still  more  strongly  emphasized,  especially  those 
relating  to  the  quantity  of  debris  derived  from  cells  undergoing 
dissolution.  While  it  is  true  that  the  above  changes  in  the  leu- 
cocytes may  be  found  in  many  cases  of  pulmonary  tuberculosis, 
they  by  no  means  occur  in  all,  nor  can  they  be  regarded  as  char- 
acteristic of  this  disease.  Any  septic  or  purulent  process  may 
cause  a  similar  polynuclear  neutrophile  increase,  while  the  pres- 
ence of  degenerating  forms  of  cells  is  not  at  all  uncommon  in 
such  conditions. 

The  numerical  variations  in  the  leucocytes  in  coxalgia,  Pott's 
disease,  and  other  forms  of  joint  and  bone  tuberculosis  are  well 
illustrated  by  the  following  analysis  of  the  large  number  of  counts 
made  by  Brown  2  and  by  Dane  3  in  these  conditions. 


Leucocytes  per  c.mm. 

Brown's  122  Counts. 

Dane's  51  Counts. 

Above  30,000  in 

1 

4 

From  20,000  to 

30,000  in  

8 

12 

"      18,000  " 

20  000  "  

4 

1 

"      16,000  " 

18,000  "  

5 

2 

"      14,000  " 

16,000  "  

16 

4 

"      12,000  " 

14,000  "  

22 

12 

"      10,000  " 

12,000  "  

18 

7 

"       9,000  " 

10,000  "  

19 

3 

"       8,000  " 

9,000  "  

9 

1 

"       7,000  " 

8,000  "  

8 

1 

"       6,000  " 

7,000  "  

8 

4 

5,000  " 

6,000  "  

4 

0 

Maximum  

3I>25° 

41,369 

Minimum  

5,100 

6,063 

1  Jour.  Amer.  Med.  Assoc.  1897,  vol.  xxix,  p.  828. 

2  Loc.  cit.  3  Loc.  cit. 


TUBERCULOSIS. 


549 


In  the  great  majority  of  instances  the  high  counts  picture  a 
polynuclear  neutrophil  leucocytosis,  but  this  is  not  invariably 
the  rule,  since  in  an  occasional  case  the  gain  depends  chiefly 
upon  an  increase  in  the  lymphocytes.  Low  counts  may  also 
be  characterized  by  a  relative  lymphocytosis,  this  change^  being 
most  common  and  most  marked  in  young  children  and  in  the 
profoundly  cachectic. 

From  the  results  of  the  studies  made  by  the  above-men- 
tioned writers  it  may  be  concluded  that  in  these  forms  of 
bone  tuberculosis  high  leucocyte  counts  generally  signify  that 
an  abscess  either  exists  or  impends,  although,  on  the  contrary, 
low  counts  do  not  necessarily  preclude  the  presence  of  an  ab- 
scess. High  counts,  especially  those  of  rapid  development, 
point  to  a  secondary  pyogenic  infection,  while  slowly  de- 
veloping, moderate  leucocytoses  appear  to  be  compatible  with 
simply  a  sudden  increase  in  the  activity  of  the  tuberculous  proc- 
ess. In  the  presence  of  an  abscess  low  counts  usually  indicate 
a  pure  tuberculous  pus  collection.  Cases  in  which,  at  the  first 
operation,  the  pus  was  proved  sterile  show  an  increased  ^  leuco- 
cyte count  when  the  wound  becomes  infected  with  pyogenic  bac- 
teria. In  these  post-operative  leucocytoses  due  to  secondary 
infection  the  count  persists  very  high  for  a  few  days,  and  then 
gradually  falls  unless  the  sepsis  is  so  acute  as  to  threaten  life,  in 
the  event  of  which  it  may  still  remain  high  until  a  crisis  is  reached. 
Should  the  pyogenic  infection  be  so  severe  as  to  overcome  the 
patient's  resisting  powers,  the  leucocytosis  either  fails  to  develop 
or  else  disappears,  if  it  is  already  present.  As  in  pulmonary 
tuberculosis,  the  leucocyte  count  and  the  degree  of  pyrexia  ap- 
parently stand  in  no  parallelism. 

Absence  of  a  leucocyte  increase  is  the  rule  in  uncomplicated 
acute  miliary  tuberculosis,  tuberculous  adenitis,  pleurisy,  and  peri- 
carditis, whereas  in  tuberculosis  of  the  genito -urinary  apparatus 
high  counts  are  not  uncommon,  owing  to  the  frequency^  of 
secondary  infections  in  such  lesions.  In  tuberculous  peritonitis, 
especially  in  early  life,  the  count  may  also  be  high,  probably 
always  as  the  result  of  coexisting  inflammatory  processes.  In 
Rotch's1  23  cases  in  young  children  the  leucocytes  averaged  16,435, 
and  ranged  between  5400  and  44,000  per  c.mm.  Such  high  counts 
as  these  rarely  occur  in  the  adult.  In  tuberculous  meningitis, 
unlike  other  forms  of  tuberculosis,  leucocytosis  is  the  rule.  It  oc- 
curred in  75  per  cent,  of  Cabot's3  43  cases,  the  counts  in  some 
cases  ranging  as  high  as  40,000  to  50,000.    Of  26  cases  of  tubercu- 

1  Jour.  Amer.  Med.  Assoc.,  1903,  vol.  xl,  p.  69.  2  Log.  cit. 


55° 


GENERAL  HEMATOLOGY. 


lous  meningitis  in  children  studied  by  Koplik,1  40  per  cent,  showed 
a  count  of  20,000  to  25,000,  results  corresponding  to  those  found 
by  Osier2  in  the  adult. 

The  presence  of  a  leucocytosis  in  a  lesion  ob- 
Diagnosis.  viously  tuberculous,  whatever  its  seat,  is  usually 
to  be  interpreted  as  a  sign  of  some  complicating 
secondary  infection,  the  chief  exceptions  to  this  general  rule  being 
those  infrequent  cases  in  which  the  sudden  extension  of  a  purely- 
tuberculous  bone  disease  may  cause  a  moderate,  progressive  rise 
in  the  count.  A  positive  iodin  reaction  also  points  to  a  mixed 
infection.  In  pulmonary  tuberculosis,  if  the  influences  of  broncho- 
pneumonia and  hemorrhage  can  be  ruled  out,  leucocytosis  almost 
invariably  indicates  the  presence  of  cavity  formation,  and  in  bone 
tuberculosis  the  superposition  of  a  pyogenic  process.  In  perito- 
neal, pleural,  and  pericardial  effusions  low  counts  suggest  an  un- 
mixed tuberculous  affection  unless  the  leucopenic  influences  of  a 
virulent  infection  are  to  be  found.  The  diagnosis  between  acute 
miliary  tuberculosis  and  enteric  fever  has  been  referred  to  under 
the  latter  disease.  (See  p.  409.)  Blood  cultures  should  be 
made  in  every  case  of  doubtful  miliary  tuberculosis,  for  posi- 
tive results,  although  rare,  are  conclusive  when  present.  The 
leucocyte  count  may  be  quite  as  high  in  tuberculous  as  it  is  in 
non- tuberculous  meningitis. 


LXXIIL  TYPHUS  FEVER. 

Lewaschew3  claims  to  have  found,  in  the 
Parasitology,  finger  blood  of  a  large  number  of  typhus  patients, 
a  micrococcus,  occurring  both  singly  and  in 
pairs,  which  he  characterizes  as  the  Micrococcus  exanthemati- 
cus,  and  regards  as  the  pathological  agent  of  infection.  A 
diplococcus  has  been  isolated  by  Balfour  and  Porter,4  from 
blood  obtained  by  puncture  of  the  thumb,  in  36  of  43 
cases  of  typhus  examined  by  these  authors.  In  a  large  num- 
ber of  control  cases,  including  measles,  scarlet  fever,  and  en- 
teric fever,  the  organism  in  question  was  uniformly  absent,  except 
in  the  last-named  disease,  in  which  it  was  discovered  in  40  of  the 
46  cases  studied.  Cultures  of  this  parasite  when  injected  intrave- 
nously into  rabbits  produced  a  rapidly  fatal  septicemia  in  these 

1  Med.  News,  1904,  vol.  lxxxiv,  p.  1065. 

2  "Principles  and  Practice  of  Medicine,"4th  ed.,  New  York,  1901. 

3  Russkiy  Vrach,  1894,  Nos.  2  and  3;  abst.  in  Sajous' Annual,  1895,  sec.  H, 
P-45- 

4  Edinburgh  Med.  Jour.,  1899,  vol.  vi,  p.  522. 


TYPHUS  FEVER. 


551 


animals.  In  6  cases  of  typhus  Gotschlich1  reports  having  found 
protozoan  bodies  resembling  Smith's  Piro plasma  bigemmum 
of  Texas  fever.  The  organisms  in  question  were  observed  m 
three  different  developmental  stages— intracellular  forms,  extra- 
cellular ovoids  and  spheres,  and  free  flagellated  bodies.  These 
investigations,  while  interesting  as  pathological  studies,  throw  no 
definite  light  upon  the  etiology  of  typhus  fever.  . 

From  the  limited  data  at  present  available  it 
Hemoglobin  appears  that  at  the  beginning  of  the  attack  the 
and         amount  of  hemoglobin  and  the  number  of  eryth- 
Erythrogytes.  rocytes  remain  unchanged,  but  that  later  a  mod- 
erate degree  of  anemia  appears,  being  most  marked 
during  the  period  of  apyrexia.    Tumas'  careful  studies2  of  two 
cases,  in  which  altogether  25  examinations  were  made,  showed  a 
hemoglobin  range  of  from  50  to  94  per  cent.,  with  from  3,450,000 
to  5,360,000  erythrocytes  per  c.mm.,  the  minimum  figures  for  both 
being  observed  during  the  second  week  of  the  infection.  The 
presence  of  structural  degenerative  changes  and  of  erythroblasts 
has  not  been  recorded.    In  the  acutest  forms  of  the  disease  hemo- 
globinemia  has  been  noted. 

Absence  of  leucocytosis,  with  occasional  counts 
Leucocytes,  showing  a  decided  leucopenia,  is  the  rule,  as  in 
enteric  fever,  according  to  conclusions  of  the 
most  careful  investigators  of  this  question.  Even  the  coexis- 
tence of  another  infection,  alone  sufficient  to  give  rise  to  leu- 
cocytosis, seems  to  have  no  effect  in  provoking  an  increase,  as 
evidenced  by  one  of  Tumas'  cases,  complicated  by  diphtheria,  in 
which  the  number  of  leucocytes  never  exceeded  9600  per  c.mm.; 
in  his  other  case  they  once  rose  to  17,000  after  a  profuse  sweat,  but 
with  this  exception  the  counts  all  ranged  between  1600  and  9600. 
Ewing3  found  a  maximum  count  of  9000  in  a  study  of  4  cases, 
2  of  which  were  fatal.  It  has  not  yet  been  determined  whether  or 
not  specific  qualitative  changes  affect  the  leucocytes  in  this  disease. 

In  differentiating  typhus  fever  from  epidemic 
Diagnosis,  cerebrospinal  meningitis  the  presence  of  a  frank 
leucocytosis  should  be  regarded  as  highly  symp- 
tomatic of  the  latter.  The  behavior  of  the  leucocytes  fails  to  be 
of  service  in  distinguishing  typhus  from  typhoid,  since  in  neither 
of  these  infections  are  these  cells  increased  in  number;  here,  how- 
ever, the  serum  test  and  blood  culturing  prove  of  signal  utility. 


1  Sem.  med.,  1903,  vol.  xxiii,  p.  298. 

2  Deutsch.  Arch.  f.  klin.  Med.,  1887,  vol.  xli,  p.  323. 

3  "  Clinical  Pathology  of  the  Blood,"  2d  ed.,  Philadelphia  and  New  York,  1904. 


552 


GENERAL  HEMATOLOGY. 


Absence  of  leukocytosis  is  also  associated  with  malignant  measles, 
the  early  stages  of  which  may  remind  one  of  typhus  fever. 


LXX1V.  VACCINATION. 

Billings1  who  has  carefully  studied  the  effects  of  vacci- 
nation on  the  blood,  finds  that  no  changes  are  produced  in  the 
hemoglobin  and  erythrocytes  by  this  procedure.  Pallor,  with  other 
signs  of  anemia,  developing  in  young  children  after  vaccination 
has  been  described  as  " post- vaccinal  anemia"  by  Bellotti,2  who 
attributes  the  change,  if  such  it  be,  to  the  hemolytic  effect  of  the 
vaccine  virus.  Bellotti's  conclusions,  since  they  are  not  fortified 
by  blood  counts,  must  be  accepted  with  doubt. 

Moderate  but  definite  leucocytosis,  the  counts  averaging  about 
15,000  per  c.mm.,  is  characteristic.  The  leucocytosis  is  of  the 
inflammatory  type,  and  reaches  its  maximum  coincidentally  with 
the  height  of  maturation  of  the  vaccine  pustule,  fading  away  as 
the  latter  desiccates.  Sobotka3  has  observed  a  secondary  leuco- 
cytosis, beginning  about  the  tenth  or  twelfth  day,  and  often  per- 
sisting for  as  long  as  six  days,  the  height  of  the  count  correspond- 
ing in  a  general  way  to  the  severity  of  the  local  lesion  and  to  the 
activity  of  the  virus. 

LXXV.  VALVULAR  HEART  DISEASE. 

In  well-compensated  valvular  lesions  of  the 
Stage  or  heart,  irrespective  of  their  character,  the  blood 
Compensation,  shows  no  deviation  from  its  normal  composition, 
for  such  lesions  of  themselves  are  incapable  of 
giving  rise  to  blood  changes.  If  the  latter  are  observed  in  cases 
of  this  kind,  they  should  be  attributed  to  other  factors  rather 
than  to  the  heart  disease. 

In  cases  associated  with  acute  failure  of  com- 
Acute  Rup-   pensation  changes  in  the  blood  picture,  the  in- 
ture  of      tensity  of  which  runs  parallel  to  the  severity 
Compensation,  of  the  circulatory  disturbances,  sooner  or  later  be- 
come manifest.    These  changes,  consisting  in  the 
production  of  a  so-called  serous  plethora,  depend  chiefly  upon  a  re- 
duction in  blood  pressure,  in  consequence  of  which  the  blood  mass 
becomes  diluted  by  transudation  into  the  vessels  of  fluids  from  the 

1  Med.  News,  1898,  vol.  lxxiii,  p.  301. 

2  Gaz.  degli  Ospedali  e.  d.  Clin.,  1903,  vol.  xxiv,  p.  587. 
?  Zeitschr.  f.  Heilk.,  1893,  vol.  xiv,  p.  349. 


VALVULAR  HEART  DISEASE. 


553 


surrounding  lymph  spaces.  It  is  also  highly  probable  that  this 
surcharging  of  the  blood  mass  with  liquids  is  aggravated  by  the 
disturbances  in  the  functions  of  the  heart  and  kidneys  whereby 
the  elimination  of  the  superfluous  watery  constituents  of  the  blood 
is  hindered.  Oertel1  remarks  that  it  seems  not  unlikely  that  an- 
other factor  in  the  production  of  this  hydremia  may  be  found  in 
the  increased  consumption  of  liquids,  which  he  has  noted  in  many 
patients  suffering  from  valvular  disease.  Examination  of  the 
blood  at  this  stage  of  the  disease  shows  that  there  is  a  diminution 
in  the  albuminoid  constituents  and  in  the  specific  gravity  of  the 
blood,  that  the  percentage  of  hemoglobin  falls,  and  that  oligo- 
cythemia proportionate  to  the  latter  develops;  the  leucocytes,  un- 
like the  erythrocytes,  do  not  decrease,  but  their  number  remains 
within  normal  limits.  The  observer  must  be  careful  not  to  mis- 
take the  blood  picture  of  hydremia  for  that  of  a  true  anemia,  from 
which  it  is  distinguishable  only  by  taking  into  consideration  other 
clinical  signs  and  symptoms.  _  2 

In  chronic  valvular  lesions,  myocarditis,  and  dilatation,  Schott 
found,  as  the  result  of  his  treatment  by  baths  and  gymnastics,  a 
decided  hemoglobin  increase.    In  the  average  case  it  amounted  to 
a  gain  of  about  20  per  cent.,  and  usually  was  associated  with  a 
blood  pressure  rise  ranging  from  20  to  30  mm.  of  mercury. 

In  cases  of  chronic  valvular  disease  with 
Effects  of    stasis,  dyspnea,  and  cyanosis,  a  very  different 
Stasis.       picture  from  that  just  described  presents  itself. 

The  hydremia  gives  way  to  a  concentration  of  the 
blood  mass,  this  change  being  due  mainly  to  the  increased  outflow 
of  plasma  from  the  vessels  into  the  neighboring  tissues,  and  per- 
haps to  the  excessive  loss  of  water,  especially  through  the  lungs, 
as  Grawitz3  has  suggested.  Stengel4  offers  as  an  explanation  of 
this  inspissation  of  the  blood  two  other  factors:  the  lagging  of 
the  erythrocytes  in  the  peripheral  arterioles  and  venules,  and  the 
increase  in  the  viscosity  of  the  blood.  Calabresse5  argues  that  in 
some  instances  the  polycythemia  may  be  absolute,  being  a  sign 
of  hematopoietic  hyperactivity  excited  by  an  excess  of  carbonic 
acid  in  the  blood.  Other  signs  of  active  hemogenesis,  such  as 
the  presence  of  normoblasts,  are  required,  however,  to  make  this 
view  reasonable. 

At  this  period  of  valvular  disease  the  specific  gravity  and 
the  proportion  of  albuminoid  principles  of  the   blood  rise, 

1  Deutsch.  Arch.  f.  klin.  Med.,  1892,  vol.  xxxi,  p.  293. 

2  Brit.  Med.  Jour.,  1904,  vol.  i,  p.  536.  Loc.  at. 

4  Proc.  Path.  Soc.  of  Phila.,  1898,  vol.  i,  p.  137. 

5  Sem.  med.,  1903,  vol.  xxiii,  p.  388. 


554 


GENEKAL  HEMATOLOGY. 


and  high  hemoglobin  values  with  more  or  less  decided  polycy- 
themia are  found,  the  erythrocyte  count  commonly  being  in  the 
neighborhood  of  6,000,000  per  c.mm.,  or,  in  some  instances,  nota- 
bly those  of  congenital  heart  disease,  as  high  as  from  7,000,000 
to  8,000,000.  It  is  common  to  find  many  mcgalocytcs,  and,  as 
Labbe  1  has  shown,  a  great  increase  in  the  proportion  of  reduced 
hemoglobin  in  the  blood.  The  polycythemia,  it  should  be  remem- 
bered, may  be  sufficient  completely  to  mask  a  coexisting  anemia;, 
in  fact,  it  must  be  admitted  that  no  reliable  data  concerning  the 
true  condition  of  the  blood  are  obtainable  in  valvular  disease  of 
the  heart,  except  during  the  stage  of  perfect  compensation. 

The  behavior  of  the  leucocytes  is  variable :  their  number  may 
be  normal,  or,  on  the  other  hand,  a  decided,  but  not  an  ex- 
cessive, leucocytosis  may  be  present.  Should  this  be  the  case, 
the  increase  will  be  found  to  involve  principally  the  polynuclear 
neutrophil  cells  at  the  expense  of  the  other  forms. 

Grawitz2  has  drawn  attention  to  the  fact  that  a  form  of 
stroma  degeneration  is  frequently  met  with  in  valvular  dis- 
ease, being  evidenced  by  the  unnatural  readiness  with  which 
the  hemoglobin  tends  to  become  diffused  in  the  plasma  within  a 
short  time  after  the  removal  of  the  blood  from  the  body.  This, 
while  it  cannot  be  termed  a  true  hemoglobinemia,  at  least  appears 
to  demonstrate  that  the  stroma  and  its  hemoglobin  are  less  firmly 
combined  than  they  are  in  perfectly  normal  blood. 

The  efforts  made  by  some  authors  to  associate  certain  blood 
conditions  with  definite  valvular  lesions  seem  to  the  writer  far- 
fetched. The  changes  just  described  are  thought  by  some  to  be 
especially  prone  to  occur  in  affections  of  the  mitral  segments, 
and  other  authors  even  go  so  far  as  to  state  that  disease  of  these 
valves  is  more  often  associated  with  transient  apparent  anemia  or 
with  chronic  polycythemia  than  lesions  of  the  aortic  valves,  the 
blood  in  the  latter  conditions  being  usually  normal  or  but  slightly 
impoverished.  After  all,  the  general  disturbances  dependent  upon 
the  lesion,  and  not  the  lesion  per  se,  account  for  the  alterations  of 
the  normal  blood  picture  which  have  been  observed  in  heart, 
disease  of  this  type. 

LXXVI.  VARICELLA. 

Thomson  and  Brownlee 3  report  having  found  small  spherical 
hyaline  bodies  in  the  blood  of  persons  suffering  from  chicken-pox,, 
both  in  the  prodromal  stage  and  during  the  first  week  of  the  disease. 


1  Sem.  med.,  1903,  vol.  xxiii,  p.  33. 

3  Brit.  Med.  Jour.,  1903,  vol.  i,  p.  241. 


Loc.  cit. 


VARIOLA. 


555 


Uncomplicated  chicken-pox  produces  no  alteration  in  the 
hemoglobin  and  erythrocytes,  but  in  cases  complicated  by  ex- 
tensive necrotic  processes  ("varicella  escharotica")  or  by  hem- 
orrhage (" varicella  hemorrhagica")  a  variable  degree  of  sympto- 
matic anemia  may  be  encountered. 

The  leucocytes  behave  erratically  both  as  to  number  and  as  to 
kind.  In  about  one-third  of  the  reported  cases  the  stage  of  active 
pustulation  was  associated  with  a  moderate  neutrophil  increase, 
ranging  from  iooo  to  4500  cells  above  normal.  In  Engel's  case, 
the  first  on  record,  this  was  accompanied  by  a  disappearance  of  the 
eosinophils,  which,  after  the  pustules  healed,  rose  to  16  per  cent. 
Practically  similar  quantitative  changes  were  found  by  Nobecourt 
and  Merklen2  in  their  series  of  15  cases,  but  in  one-half  the  large 
lymphocytes  were  in  excess  and  myelocytes  were  noted  in  one- 
third.  In  contrast  to  these  findings,  Weil  and  Descos,  while 
meeting  with  polynuclear  neutrophile  leucocytosis  in  about  one 
case  in  three,  deny  that  either  lymphocytosis  or  myelocytes^  is 
found  in  varicella,  and  emphasize  the  value  of  this  negative 
finding  as  a  sign  for  differentiating  this  condition  from  small-pox. 
Stengel  and  White4  report  normal  leucocyte  counts  in  uncom- 
plicated cases. 

It  is  obvious  that  the  contradictory  reports  of  various  obser- 
vers must  be  reconciled  by  further  investigation  before  the  blood 
examination  in  varicella  can  have  any  dependable  clinical  bearing. 


LXXVII.  VARIOLA. 
During  the  first  few  days  of  the  attack  the 
General     fibrin  network  is  normal,  but  as  the  stage  of  pus- 
Features,     tular  eruption  is  reached,  a  decided  hyperinosis 
develops.    Streptococci  have  been  found  in  the 
blood  repeatedly  by  Widal  and  Benzacon,5  and  also  by  Waele  and 
Sugg.6    The  streptococcus  found  by  the  last-named  authors  is 
clumped  by  variolous  blood  serum  and  by  that  of  successfully  vac- 
cinated subjects,  but  not  by  the  serum  of  unvaccinated  persons  nor 
by  ordinary  antistreptococcus  serum.    Pfeiffer7  has  attached  spe- 
cific properties  to  apparently  ameboid  bodies  which  he  discovered 
in  small-pox  patients'  blood,  and  to  this  view  a  number  of  other 

1  XV.  Cong.  f.  inn.  Med.,  1897. 

2  Jour,  de  physiol.  et  de  path,  gen.,  1901,  vol.  iii,  p.  439- 

3  Ibid.,  1902,  vol.  iv,  p.  504. 

4  Univ.  of  Penna.  Med.  Bull.,  1901,  vol.  xiv,  p.  310. 

5  Centralbl.  f.  allg.  Path.,  1896.  vol.  vii,  p.  569. 

6  Brit.  Med.  Jour.  Epit.,  1904,  vol.  i,  p.  8. 

7  "Handb.  d.  spec.  Therap.,"  1894,  vol.  i,  p.  229. 


GENERAL  HEMATOLOGY. 


workers,  notably  Guarnicri1  and  Wasielewski,2  also  subscribe. 
Other  amebae  have  been  found  under  similar  circumstances  by 
Reed,3  Weber,4  Ishigami,5  Thomson  and  Brownlee,6  and  others. 
None  of  these  discoveries  has  elucidated  the  etiology  of  variola. 
A  protozoan  body  (Cytoryctes  variola)  has  been  found  in  the 
skin  epithelium  and  once  in  the  blood  of  small-pox  patients  by 
Councilman,  Magrath,  and  Brinckerhoff,7  who  consider  this  or- 
ganism the  specific  cause  of  the  disease.  This  claim,  although 
based  upon  convincing  experimental  work,  has  still  to  endure 
the  test  of  corroborative  research. 

Post-febrile  anemia,  first  becoming  apparent 
Hemoglobin  when  defervescence  is  established,  is  the  rule, 
and         the  decrease  in  hemoglobin  and  corpuscles  being 
Erythrocytes,  usually  decided,  and  not  infrequently  excessive. 

This  is  especially  true  in  hemorrhagic  and  con- 
fluent variola,  in  which  conditions  a  loss  of  2,000,000  or  3,000,- 
000  cells  per  c.mm.  may  occur  with  great  rapidity.  The  loss 
of  hemoglobin  begins  slightly  earlier  than  that  of  the  corpuscles, 
but  later  both  elements  are  usually  diminished  proportionately. 

During  the  febrile  period  of  the  disease  the  number  of  erythro- 
cytes is  approximately  normal,  or  even  increased,  in  case  the 
blood  becomes  concentrated  by  the  influence  of  the  temperature. 

Qualitative  changes  in  the  erythrocytes  are  not  marked,  except 
in  cases  with  severe  anemia,  in  which  nucleation,  poikilocytosis, 
and  deformities  of  size  may  be  noted.  In  such  instances  hemo- 
globinemia  may  also  occasionally  be  detected.  Regeneration  of 
the  blood  is  said  to  be  exceedingly  slow. 

In  the  majority  of  cases  a  moderate  but 
Leucocytes,  distinct  leucocyte  increase  develops,  first  becom- 
ing apparent  in  the  early  stages  of  the  dis- 
ease, reaching  its  maximum  during  pustulation,  and  gradu- 
ally declining  during  desiccation  of  the  pocks,  unless  prolonged 
by  some  complication.  In  the  uncomplicated  case  the  normal 
count  is  regained  by  the  end  of  the  second  or  the  early  part  of 
the  third  week.  The  count  usually  ranges  between  10,000  and 
20,000,  although  such  factors  as  hemorrhage,  confluence,  and 
secondary  infection  tend  to  exaggerate  these  figures.    In  a  series 

1  Arch,  per  le  sci.  med.,  1897,  vol.  xvi,  p.  403. 

2  Zeitschr.  f.  Hyg.  u.  Infectionskr.,  1901,  vol.  xxxviii,  p.  212. 

3  Jour.  Exper.  Med.,  1897,  vol.  ii,  p.  515. 

4  Centralbl.  f  Bakt.  u.  Parasit.,  1897,  vol.  xxi,  p.  286. 

5  Ibid.,  1902,  vol.  xxxi,  p.  794.  6  Brit.  Med.  Jour.,  1903,  vol.  i,  p.  241 
7  Jour.  Med.  Research,  1903,  vol.  iv,  p.  372;  ibid.,  1904,  vol  xi,  p.  12;  also 

Calkins,  ibid.,  p.  136. 


VARIOLA. 


557 


of  36  cases  studied  by  Roger1  the  count  ranged  from  6000  to 
15,000  in  19;  from  15,000  to  20,000  in  12;  from  20,000  to  30,000 
in  3;  and  from  30,000  to  35,000  in  2.  The  count  is  likely  to  be 
higher  in  the-unvaccinated  than  in  the  vaccinated,  and  may  rapidly 
diminish  under  the  influence  of  serum  therapy,  and,  in  some  fatal 
cases,  just  before  death. 

The  behavior  of  the  leucocytes  in  small-pox  is  probably  due  to 
the  action  of  the  specific  variolous  toxin,  which,  if  sufficiently  active, 
provokes  an  increase  of  these  cells.  This  change  develops  too 
early  in  the  disease  to  be  dependent  solely  upon  the  effects  of 
secondary  infection  of  the  pocks,  which  accident  the  older  writers- 
Pick,2  Halla,2  Brouardel,2  and  others— maintained  was  the  real 
determining  factor.  Furthermore,  the  increase  involves  chiefly 
the  large  lymphocytes,  which  cells,  according  to  Courmont  and 
Montgard,3  are  in  excess  even  when  there  is  extensive  streptococcic 
pustulation  of  the  lesions;  when,  however,  genuine  secondary 
furunculosis  and  abscesses  complicate  the  variolous  process,  a 
neutrophil  leucocytosis  promptly  supervenes.  These  findings, 
which  have  been  corroborated  by  Weil,4  by  Ewing,5  and  by 
Roger,6  strongly  suggest  that  pustulation  is  a  specific  change, 
and  not  merely  the  expression  of  a  secondary  contamination  of 
the  pocks  with  pyogenic  bacteria,  as  was  the  former  belief.  Myelo- 
cytes, sometimes  in  considerable  numbers,  are  also  found  with 
great  constancy,  and  are  especially  abundant  in  the  severer  types 
of  the  infection.  The  eosinophiles  may  be  greatly  increased  in 
hemorrhagic  small-pox,  and  small  percentages  of  mast  cells  are 
to  be  noted  in  cases  with  high  leucocyte  counts. 

.  The  blood  plaques  are  decreased  in  number  during  the  period 
of  fever,  being  sometimes  absent  from  the  blood  at  this  stage  of 
the  disease. 

Varioloid,  unless  associated  with  suppuration,  does  not  give  rise 
to  anemia  nor  to  leucocytosis. 

The  presence  of  a  definite  mononucleosis,  in- 
Diagnosis.  volving  principally  the  large  lymphocytes  and  the 
myelocytes,  is  highly  suggestive.  Such  a  blood 
picture  is  sufficient  evidence  to  exclude  measles,  for  which  the 
prepustular  stage  of  variola  has  been  mistaken,  and  to  suggest 
true,  rather  than  modified,  small- pox.  In  pustular  syphilide  and 
in  the  purpuric  type  of  cerebrospinal  meningitis,  which  may  coun- 
terfeit variola,  the  blood  shows  a  typical  polynuclear  neutrophil 

1  "Infectious  Diseases,"  Eng.  trans,  by  Gabriel,  New  York  and  Philadelphia, 

1903,  p.  260.  2  Cited  by  von  Limbeck,  loc.  cit 
^Province  med.,  1900,  vol.  xv,  p.  481.        4  Sem.  med.,  1900,  vol.  xx,  p.  222. 
5  "Clinical  Pathology  of  the  Blood,"  New  York  and  Philadelphia,  2d  ed. 

1904,  p.  296.  6  Loc.  cit. 


558 


GENERAL  HEMATOLOGY. 


leucocytosis.  Owing  to  the  current  conflicting  views  (see  p.  555) 
it  is  impossible  at  present  to  base  the  differentiation  of  variola 
and  varicella  upon  the  state  of  the  blood. 


LXXVIII.    YELLOW  FEVER. 

Slow  coagulation  and  deficiency  or  even  com- 
General     plete  absence  of  the  fibrin  network  are  common, 

Features,  these  peculiarities  being  observable  often  in  the 
earliest  stages  of  the  disease,  apparently  beginning 
coincidentally  with  the  introduction  of  the  infecting  principle. 

The  identity  of  the  specific  cause  of  this  disease  is  still  un- 
known. Sanarelli's  claim,1  that  his  Bacillus  icteroides  is  to  be 
found  in  the  circulating  blood  of  yellow  fever  patients  during  life, 
has  been  very  generally  disproved.  Reed  and  Carroll2  have  shown 
that  this  bacterium  is  identical,  morphologically  and  biologically, 
with  the  hog-cholera  bacillus,  and  Agramonte 3  and  the  members 
of  the  United  States  Yellow  Fever  Commission4  (Reed,  Carroll, 
Agramonte,  and  Lazear)  report  uniform  failures  to  isolate  Sana- 
relli's bacillus  either  by  antemortem  blood  cultures  or  by  post- 
mortem examinations  of  the  blood  and  organs  of  persons 
dead  of  yellow  fever.  In  passing,  it  may  be  of  interest  to 
add  that  Finlay's  theory,5  that  yellow  fever  is  transmitted  by 
means  of  the  mosquito's  bite,  has  been  confirmed  beyond  question 
by  the  experiments  of  this  Commission,  which  has  identified  the 
Stegomyia  jasciata  as  the  offending  insect.  The  French  Yellow 
Fever  Commission6  has  fully  corroborated  these  findings.  The 
character  of  the  infective  principle  thus  harbored  by  the  mosquito 
is  unknown — possibly  it  belongs  to  that  class  of  invisible  (ultra- 
microscopic)  organisms  now  believed  to  excite  certain  specific 
infections.  Finlay7  suggests  that  it  may  be  a  protozoon  similar 
to  the  malarial  plasmodium,  which  undergoes  one  developmental 
cycle  in  the  human  body  and  another  in  the  mosquito,  the  former 
being  an  asexual  reproduction  accompanied  by  the  elaboration  of 
powerful  toxins  to  which  the  fever  is  to  be  attributed.    J.  C. 

^nnal.  de  l'lnstitut  Pasteur,  1897,  vol.  xi,  p.  433;  also  Brit.  Med.  Jour., 
1897,  vol.  ii,  p.  7;  also  Med.  Record,  1897,  vol.  lxii,  p.  117. 

2  Jour.  Exper.  Med.,  1900,  vol.  v,  p.  216;  also  Carroll,  N.  Y.  Med.  Jour., 
1904,  vol.  lxxix,  p.  241.  3  Med.  News,  1900,  vol.  lxxvi,  p.  249. 

4  Phila.  Med.  Jour.,  1900,  vol.  vi,  p.  790;  also  Jour.  Amer.  Med.  Assoc.,  1901, 
vol.  xxxvi,  p.  431. 

5  Jour.  Amer.  Med.  Assoc.,  1901,  vol.  xxxvi,  p.  1040. 

6  Jour.  Amer.  Med.  Assoc.,  1904,  vol.  xlii,  p.  1369. 

7  Lancet,  1903,  vol.  i,  p.  171 1. 


YELLOW  FEVER. 


559 


Smith1  and  Parker,  Beyer,  and  Pothier2  have  discovered  what 
they  regard  as  a  protozoan  parasite,  called  by  them  the  Myxococ- 
cidium  stegomyice,  in  the  bodies  of  Stegomyia  fasciata  fed  upon 
the  blood  of  yellow  fever  patients,  but  in  no  others.  The  inference 
from  their  announcement,  that  these  bodies  represent  the  specific 
cause  of  yellow  fever  undergoing  its  mosquito  phase,  has  been 
weakened  considerably  by  Carroll's  later  and  apparently  convinc- 
ing demonstration3  that  the  so-called  protozoon  is  merely  a 
yeast  fungus  such  as  is  commonly  found  in  the  mosquito  fed  upon 
overripe  bananas  to  which  yeast  has  been  added. 

In  a  series  of  23  cases  Tombleson4  claims  to  have  found  in 
finger  blood  peculiar  polymorphous  organisms,  appearing  as 
short  oval  bacilli,  as  bacilli  with  rounded  ends,  and  as  long  beaded 
rods. 

Pothier's  studies  of  154  cases  at  the  New 
Hemoglobin  Orleans  Isolation  Hospital,  in  1897,5  show  that  a 
and  more  or  less  decided  loss  of  hemoglobin  com- 
Erythrocytes.  monly  occurs  during  the  active  stages  of  the  in- 
fection, and  that  the  normal  percentage  is  slowly 
regained  during  and  after  convalescence;  during  the  febrile  period 
the  hemoglobin  ranged  from  50  to  90  per  cent.,  and  during  con- 
valescence from  64  to  80  per  cent.  He  found  that  the  erythro- 
cyte count  never  fell  below  4,280,000  per  c.mm.,  and  that  even 
in  a  fatal  case  it  might  be  normal.  Lack  of  parallelism  between 
the  hemoglobin  percentage  and  the  specific  gravity  of  the  blood 
is  a  peculiarity  to  which  Albertini6  has  drawn  attention,  this 
investigator  having  repeatedly  noted  a .  considerable  fall  in  the 
blood  density  without  a  corresponding  loss  of  hemoglobin.  Stern- 
berg7 has  noted  the  absence  of  quantitative  changes  affecting  the 
erythrocytes  in  this  disease,  stating  that,  u  although  there  is  no 
general  destruction  of  the  red  corpuscles,  it  is  probable  that  a  con- 
siderable number  of  these  elements  perish,  for  the  serum  contains 
free  hemoglobin,  which  gives  it  a  yellow  color  even  as  early  as  the 
third  or  fourth  day."  This  hemoglobinemia  is  common  in  all 
cases,  but  especially  so  in  fatal  cases  just  before  death.  The  re- 
sults of  these  investigations  by  Pothier  and  by  Sternberg  are  con- 
tradictory to  the  views  expressed  by  earlier  writers,  who  have  been 

1  Science,  1903,  vol.  xviii,  p.  530. 

2  Report  of  Working  Party  No.  1,  Yellow  Fever  Institute,  P.  H.  and  M.  H.  S., 
Washington,  1903. 

3  Jour.  Amer.  Med.  Assoc.,  1903,  vol.  xli,  p.  1341. 

4  Lancet,  1903,  vol.  ii,  pp.  594  and  1781. 

5  Jour.  Amer.  Med.  Assoc.,  1898,  vol.  xxx,  p.  885. 

6  Rev.  de  Med.  Trop.,  1903,  vol.  iv,  p.  73 

7  U.  S.  M.  H.  Service  Report  on  the  Etiology  and  Prevention  of  Yellow  Fever, 
Washington,  1890. 


56° 


GENERAL  HEMATOLOGY. 


accustomed  to  describe  the  cellular  elements  of  the  blood  in  yellow 
fever  as  profoundly  altered. 

Decided  degenerative  changes  in  the  erythrocytes  have  not  been 
observed,  although  it  has  been  asserted  by  Jones1  that  these  cells 
"present  under  the  microscope  certain  peculiar  appearances  which 
are  referable  to  the  action  of  certain  extraneous  excretory  matters 
in  the  blood."  A  few  nucleated  cells  of  the  normoblastic  type  are 
reported  to  have  been  found  occasionally. 

The  behavior  of  the  leucocytes  in  yellow  fever 
Leucocytes,  is  extremely  variable,  their  number  being  sub- 
normal in  some  cases,  and  decidedly,  but  not 
strikingly,  increased  in  others.  In  the  series  of  Pothier,  just  quoted, 
the  counts  ranged  between  4660  and  20,000  per  c.mm.  In  five 
counts  by  John  Guiteras2  the  leucocytes  ranged  from  3200  to 
11,400  per  c.mm.,  averaging  5400.  The  increase,  when  present, 
involves  chiefly  the  polynuclear  neutrophiles,  the  relative  propor- 
tion of  these  cells  usually  being  in  excess  of  85  or  90  per  cent.  Small 
numbers  of  myelocytes  were  found  occasionally  by  Cabot3  in  dif- 
ferential counts  of  12  films  of  yellow  fever  blood. 

Sternberg4  has  described  certain  relatively  large,  highly  refrac- 
tive, spherical  granules  in  the  protoplasm  of  the  leucocytes,  which 
he  is  inclined  to  regard  as  an  evidence  of  fatty  degeneration  of 
these  cells;  these  granules  were  especially  abundant  in  severe 
cases,  nearly  every  leucocyte  containing  some  of  them.  They  are 
not,  however,  peculiar  to  yellow  fever,  since  they  have  been  found 
in  the  blood  of  patients  suffering  from  beri-beri,  and  even  in  the 
blood  of  normal  individuals,  residents  of  the  tropics. 

Until  the  cause  of  yellow  fever  is  discovered, 
Diagnosis,  the  blood  examination  can  afford  little  or  no  aid 
in  the  recognition  of  this  infection.  The  fre- 
quency of  hemoglobinemia  in  yellow  fever,  and  its  absence,  so  far 
as  is  known,  in  dengue,  may  serve  as  a  hint  of  some  importance 
in  differentiating  these  two  fevers.  In  differentiating  malarial 
fever,  the .  examination  of  the  blood  for  the  malarial  parasite  will 
usually  give  definite  information,  and  the  occasional  presence  of 
a  well-developed  polynuclear  leucocytosis  in  yellow  fever  should 
not  be  forgotten.  The  lack  of  relationship  between  the  specific 
gravity  and  the  hemoglobin  value  of  the  blood  in  the  latter  is  also 
significant. 

1  Jour.  Amer.  Med.  Assoc.,  1895,  vol.  xxiv,  p.  403. 

2  Brit.  Med.  Jour.,  1902,  vol.  i,  p.  366.  3  Loc.  cit.  4  Loc.  cit. 


INDEX  OF  AUTHORS. 


Abbott,  402,  445 
Achalme,  14S 
Achard,  373 
Adami,  111,  146 
Adams,  539 
Addison,  365 
Afanassiew,  148,  515 
Affleck,  493 
Agramonte,  558 
Aiello,  427 
Albertini,  559 
Aldridge,  484 
Allbutt,  275 
Allen,  395 
Almazia,  471 
Altmann,  208 
Amalgia,  199 
Ames,  248 
Anderson,  531 
Aoyoma,  377 
Aporti,  162 
Appelbaum,  545 
Archard,  433 
Arloing,  542 

Armand-Delille,  179,  353 
Arneth,  290 
Arnold,  199,  214 
Arsamaskoff,  485 
Aschoff,  154 
Ashford,  440 
Askanazy,  132,  439 
Atkinson,  537 
Aubertin,  312 
Auche,  513 
Audibert,  510 
Auerbach,  130,  394 


Baccarani,  512 
Baginsky,  349,  521 
Bain,  171,  225 
Baker,  538 
Baldy,  165 

Balfour,  148,  420,  441,  550 
Ballance,  335 
Bancroft,  419 
Bannatyne,  372 
Barker,  208 

Bassett-Smith,  392,  484 


Bastian,  413 
Bastianelli,  445 
Baumann,  95,  163,  301 
Baumgarten,  73 
Baumholtz,  545 
Beaton,  518 
Beaujard,  312 
Beck,  122,  128,  543 
Becker,  132,  510 
Becker,  E.,  439 
Beco,  506 
Becquerel,  141,  436 
Behier,  300 
Bellotti,  552 
Benario,  81 
Benda,  319 
Bendix,  543 
Bennett,  306 
Bensaude,  322,  373 
Bentley,  441,  443 
Benzacon,  242,  555 
Berend,  129 
Bernard,  254 
Besredka,  251,  387 
Bettencourt,  539 
Bettman,  426 
Beyer,  559 
Bibb,  444 

Bierfreund,  164,  301,  474 

Biernacki,  267,  275,  373 

Bignami,  445,  457,  467,  469 

Billings,  321,  322,  375,  387,  469,  509, 

552 
Birk,  252 
Bize,  387 
Bizzozero,  199 
Bjorkman,  234 
Blake,  235,  421 
Blix,  91 
Bloch,  351 

Bloodgood,  244,  369,  441 
Blumer,  366,  537 
Boeckman,  209 
Boeni,  252 
Boggs,  135 

Bohland,  232,  251,  262 
Bojanus,  252 
Bordet,  113,  117 
Borini,  251 


36 


56i 


562 


INDEX  OF 


AUTHORS. 


Boston,  444,  497 
Bouchut,  387 
Boudou,  211 
Bowie,  524 
Boycott,  440 
Bra,  497 

Bradford,  321,  350 

Bradley,  350 

Bramwell,  270,  379,  488 

Brandenberg,  129,  512 

Brat,  135 

Bremer,  384 

Breuer,  164 

Brieger,  527 

Brinckerhoff,  556 

Brodie,  91 

Brooks,  537 

Brossa,  498 

Brouardel,  392,  557 

Brown,  E.  J.,  312 

Brown,  P.  K.,  262,  444,  546,  548 

Brown,  T.  R.,  256,  257,  536 

Brownlee,  554,  556 

Bruce,  484,  496,  538 

Bryant,  312 

Buard,  543 

Buchner,  238,  252 

Buff  a,  533 

Bunge,  162 

Burmin,  129,  268,  307 

Burr,  498 

Burrows,  249,  495 

Busquet,  394 

Buxton,  394 


Cabot,  184,  194,  227,  235,  244,  262, 
269,  282,  285,  305,  308,  365,  369,  382, 
421,  487,  491,  502,  512,  520,  534,  537, 

549,  56° 
Cadet,  176 
Calabresse,  553 
Calvert,  420 
Campbell,  178 
Canard,  129 

Canon,  256,  258,  380,  436,  527 

Cantani,  131,  372,  428 

Capps,  173,  222,  249,  321,  322,  494 

Carpenter,  350 

Carrara,  104 

Carriere,  375 

Carroll,  558 

Carstanjen,  231 

Carter,  387 

Cassel,  350 

Castellani,  394,  437,  539 
Castellino,  185 
Cattell,  104 
Cazeaux,  178 
Cazin,  252,  370 


Ceconi,  104 

Celli,  445 

Cevidalli,  512 

Chadbourne,  248 

Chantemesse,  410 

Charcot,  39 

Charles,  484 

Charon,  350 

Charrin,  113 

Charteris,  163 

Chausse,  497 

Cheney,  537 

Chenzinsky,  87 

Childs,  331 

Chowning,  531 

Christian,  534 

Christophers,  442,  469,  470 

Christy,  413,  452 

Churchill,  354 

Cionini,  506 

Class,  148,  521 

Clerc,  259,  420,  433 

Cobb,  531 

Cohn,  292 

Cole,  394,  506 

Coleman,  394 

Coles,  420,  441 

Combe,  485 

Copeman,  277 

Corthorn,  376 

Coste,  370 

Councilman,  445,  556 

Courmont,  394,  513,  542,  5 

Cox,  485 

Coyon,  518 

Craig,  148,  445,  485 

Crajkowski,  522 

Crane,  312 

Crisafi,  502 

Cunliffe,  476 

Cunningham,  442 

Curry,  179 

Curschmann,  370,  395 
Czerniewski,  526 
Czerny,  334,  336 


Da  Costa,  165,  248 

Daland,  91 

Dale,  534 

Dane,  546,  548 

Daniels,  82,  471,  538,  541 

Dare,  40,  98 

Darguinj  433 

Darwin,  118 

Daunay,  175 

Davidson,  414 

Dawson,  302 

De  Amicis,  502 

Decastelle,  261 


INDEX  OF 


Deetjen,  19S 
Delafield,  87 
Delany,  471 
Delbert,  305 
Delestre,  356 
Delezene,  263 
De  Lisle,  532 
Denig6,  145 
Denys,  430 
Derlin,  383 
De  Rienzi,  252,  434 
De  Saussure,  414 
Descos,  555 
Desevres,  131 
Determann,  90 
Devlin,  383 
De  Vries,  122 
De  Witt,  280 
Diabella,  133,  276 
Diefendorf,  494 
Dinkelspiel,  117,  121 
Dionisi,  466,  469 
Dobrovici,  210 
Dock,  323,  379,  445 
Donovan,  442 
D'Orlandi,  262 
Douglas,  239,  441 
Douglas,  Carstairs,  135 
Drake,  537 

Drouin,  129,  131,  393,  410 
Dubroisay,  387 
Ducchesi,  199 
Dudgeon,  433 
Dumoulin,  336 
Duncan,  541 
Dunlop,  379 
Dunn,  277,  414 
Durham,  68,  113 
Dutton,  538,  540 
Dutzmann,  370 
Duval,  425 


Ebstein,  321 
Egger,  178 

Ehrlich,  76,  81,  83,  87,  151,  188,  192, 
196,  208,  222,  224,  228,  238,  241, 
253,  262,  282,  302,  316,  419,  439,  502, 
512 

Ehrnrooth,  122 
Eichhorst,  183 
Einhorn,  73,  350,  422 
Ekgren,  234 
Elder,  280 
Elliott,  513 
Emerson,  73 

Engel,  96,  129,  195,  199,  389,  555 
Engelhardt,  122 
Erving,  365,  372 
Eubank,  301 


AUTHORS.  563 

Ewing,  118,  141,  248,  365,  387,  389,  506, 
534,  55*>557 


Fajardo,  492 
Federmann,  370 
Fehleisen,  410 
Fehrsen,  174 
Feinberg,  473 
Felsenthal,  387,  523 
Ficker,  401 
File,  387 
Filetti,  445 
Fink,  374 
Finlay,  558 
Fischl,  343 
Fleischer,  290,  304 
Flexner,  391,  513 
Foa,  179 
Fodor,  412 
Foerster,  534 
Ford,  147 
Forde,  538 
Fraenkel,  321 
Francine,  422 
Frazier,  244,  245 
French,  369 
Freudberg,  129 
Freund,  143 
Friedlander,  234 
Frohlich,  502 
Funke,  269,  393 
Fussell,  321 

Futcher,  88,  142,  228,  391,  424,  447;  5 12 


Gabritschewsky,  238,  374,  387 

Garrod,  144,  426 

Gaylord,  473 

Geissler,  350 

Gemelli,  395 

Georgiewsky ,  512 

Gerhardt,  304 

Gerngross,  370 

Gibson,  199,  382 

Gilbert,  350,  387,  436 

Gilmour,  484 

Giorgi,  426 

Girvin,  165 

Gley,  134 

Goadby,  392 

Goldberger,  226 

Goldhorn,  88 

Goldscheider,  238,  240,  250 
Golgi,  445 
Golla,  383 
Gollasch,  256 
Goodall,  232,  496 
Gordinier,  537 
Gotschlich,  551 


564 


INDEX   OF  AUTHORS. 


Gould,  537 

Gowers,  52,  69 
Gozdzicki,  545 
Gradwohl,  521 
Graeber,  268 
Graham,  382 
Graham-Smith,  120 
Gram,  172 
Grassi,  445 
Gratea,  350 

Grawitz,  179,  196,  209,  271,  307,  365, 
383,  392,  428,  431,  436,  439,  482,  491, 
S"i  5i2,  513,  527,  553,  554 

Greenbaum,  404 

Greene,  282,  397 

Greenough,  424 

Griesinger,  440 

Gros,  370 

Grosch,  312 

Griiber,  113 

Grunbaum,  117  ' 

Guarnieri,  556 

Guinard,  544 

Guinon,  350,  351 

Guiteras,  414,  560 

Gulland,  227,  232,  369,  420 

Gumbel,  379 

Gumprecht,  276 

Gundobin,  231,  344 

Gunther,  112 

Gutig,  406 

Gwyn,  395,  488,  537 


Haesslin,  300 
Hagen,  338 
Haig,  55 
Haines,  115 

Haldane,  53,  122,  125,  440 
Hall,  301,  382 
Halla,  209,  557 
Hallin,  532 

Hamburger,  106,  122,  181 
Hamel,  196,  512 
Hamill,  348 
Hamman,  321 

Hammerschlag,  94,  133,  268,  342,  521 

Hand,  252 

Hankin,  209,  252 

Hannes,  234 

Hanot,  432 

Hardy,  215,  441 

Hare',  510 

Harris,  221,  394 

Hartley,  336 

Hartmann,  334,  335 

Hartung,  477 

Hastings,  87 

Haushalter,  351 

Hawke,  176 


Hay,  392 
Haycraft,  96 

Hayem,  56,  136,  171,  172,  174,  176,  177, 
181,  183,  199,  209,  278,  287,  300,  342, 
343,  409,  430,  432,  476,  490,  512,  513, 
523 

Head,  247,  354 
Heanley,  425 
Heaton,  335 
Hedin,  91 
Heidenreich,  517 
Heim,  199,  510 
Hektoen,  522 
Henderson,  175,  233 
Henri,  167 
Henry,  414,  419,  474 
Herrick,  521 
Herscher,  436 
Hess,  321 
Hewes,  85 
Hewetson,  445 
Hewlett,  394 
Heyl,  142 
Hibbard,  233 
Higley,  408 
Hills,  279 
Hirsch,  122,  128 
Hirschfeld,  351 
Hirschlaff,  527 
Hirt,  251 
Hitschmann,  290 
Hoagland,  178 
Hofbauer,  227 
Hoffman,  477 
Hofmeister,  232 
Hollo  way,  245 
Holman,  249,  512 
Holmes,  87,  548 
Holt,  348 

Hoppe-Seyler,  143,  169,  383 
Horder,  54 
Houston,  489 
Howard,  447,  537 
Howell,  199 
Hubbard,  235,  421 
Hubner,  439,  505 
Huger,  534 
Hunt,  347 

Hutchinson,  347,  350,  428,  518 


Immerman,  300,  427 
Ishigami,  556 
Israel,  188 
Ivanoff,  517,  544 


Jacob,  238,  240,  250 

Jacques,  385,  521 

James,  482,  490,  506,  527 


INDEX  OF  AUTHORS. 


565 


Japha,  231,  350 
Jeffries,  129 
Jehle,  437-  5 22 
Jellinek,  162 
Jenner,  82 
Jennings,  376 
Jochmann,  522 
Joffroy,  276 
Johnson,  496 
Johnston,  395,  398 
Jolles,  122 
Jolly,  350,  351 

Jones,  Lloyd,  132,  139,  267,  268,  275 
Jopson,  321 
Joseph,  532 
Joslin,  424 

Joy,  369 
Justus,  533 


Kalteyer,  248 
Kalyapin,  517 
Kaminer,  226,  227 
Kanthack,  205,  209,  215,  252 
Karnizki,  344 
Kast,  406 

Kazarinoff,  395,  544 
Kelly,  304,  321 
Kelsch,  305,  468,  469 
Kemp,  179 
Kerr,  394,  536 
King,  245,  446 
Kinsey,  506 
Kippel,  495 
Kirikow,  432 
Kisch,  498 
Kitasato,  376 
Klebs,  199,  532 
Klein,  436 
Kline,  539 
Klotzsch,  532 
Knapp,  393 

Knopfelmacher,  176,  234 
Knox,  390 
Kobert,  512 
Koblanck,  261 
Koch,  543 
Kochler,  404 
Koehler,  434 
Koenigstein,  404 
Koeppe,  103,  178,  179 
Kohn,  506 
Kolisch,  228 
Kolle,  113 
Kolliker,  188 
Koplik,  487,  550 
Koranyi,  103 
Kormoczi,  290 
Korowicki,  520 
Kotchetkoff,  523 


Kraepelin,  488 
Kraus,  96,  131,  482,  506 
Krause,  395,  413 
Krauss,  527 
Kretz,  485 
Krokiewicz,  472 
Kronig,  512 
Kruse,  391 
Krusman,  251 
Kucharzewski,  389 
Kuhlman,  497 
Kuhn,  370 

Kuhnau,  394,  437,  482,  527 
Kummel,  103 
Kurloff,  336 
Kurpjuweit,  259,  480 


Laache,  300,  490 

Labbe,  206,  224,  242,  253,  353,  554 

Lacassagne,  512 

Laker,  122 

Lamb,  134,  428,  513 

Lambert,  121,  437 

Landi,  506 

Landois,  96 

Lang,  435,  475 

Lapique,  172 

Laporte,  73,  87 

Laptschinski,  516 

Larrabee,  234 

Latham,  349 

Launois,  433 

Laveran,  443,  445,  539 

Lay  ton,  118 

Lazarus,  76,  419 

Lazear,  88,  482,  558 

Lear,  121 

Le  Breton,  488 

Le  Conte,  165 

Ledingham,  442 

Lefas,  495 

Lehmann,  129 

Leichtenstern,  441,  498 

Leishman,  82,  442,  538 

Lenoble,  278,  296,  430 

Lepine,  129,  143,  254 

Leredde,  511 

Lesieur,  394 

Lessage,  391 

Letzerich,  428 

Leube,  290 

Levene,  438 

Levy,  94,  426 

Lewaschew,  550 

Lewis,  225 

Libman,  395,  403 

Lichtwitz,  375 

Lichty,  133,  291,  422 

Liebreich,  96 


566 


INDEX  OF  AUTHORS. 


Lilienfeld,  199 
Lindenthal,  192,  512 
Litten,  196,  281,  290 
Locke,  227,  370,  378 
Loeper,  478 
Loffler,  85 
Longcope,  332,  395 
Longridge,  369,  433 
Lostorfer,  532 
Lothrop,  414 
Louste,  478 
Lovibond,  49 
Low,  414,  442,  541 
Lowenbach,  533 
Lowenthal,  516 
Lowit,  199,  240,  250,  305,  481 
Lowy,  129,  238,  296,  412,  512 
Lubowski,  403 
Luce,  290 
Luciani,  261  , 
Lussana,  439 
Lustgarten,  532 
Luxemberg,  493 
Lyon,  247 


MacCallum,  447,  454 
MacPhail,  494,  497 
Mackenzie,  151 
Mackie,  522,  524 
Magrath,  556 
Mallory,  522 
Mannaberg,  445,  457 
Manson,  413,  415,  419,  442,  445,  484, 
538 

Maragliano,  122,  185,  412,  473 

Marchand,  442 

Marchetti,  544 

Marchiafava,  445,  457,  467 

Marestang,  180 

Marie,  178 

Martin,  512 

Martineau,  532 

Marx,  122 

Mastin,  414 

Mathias,  434 

Mayer,  167 

McCaw,  350 

McCrae,  311,  350,  372,  474,  519 

Meinert,  482 

Meissl,  341 

Meissner,  179 

Melkich,  517 

Memmi,  250,  433 

Mendelson,  238 

Merklen,  555 

Mertins,  534 

Metschnikoff,  113,  206,  239,  445 
Meunier,  432,  502 
Meyer,  121,  179,  251 


Mieschcr,  48 

Mikulicz,  164,  242 

Milian,  250,  433 

Miller,  321 

Minkowski,  383 

Mitchell,  J.  K.,  176,  234,  497 

Mitchell,  S.W.,  128,  513 

Mixa,  321 

Mongour,  543 

Monisset,  481 

Montagard,  557 

Monti,  352 

Morse,  345,  346,  348,  349,  354,  386, 

Mosler,  329 

Muir,  224,  241,  429 

Miiller,  200,  304,  316,  349,  511 

Murray,  488 

Musser,  332,  484 

Mya,  129 


Nattan-Larrier,  542 
Neave,  442 
Nebarro,  538 
Neisser,  383 
Nepveu,  538 
Netter,  380,  432 
Neufeld,  395 
Neuman,  537 
Neumann,  188,  527 
Neusser,  228,  257,  498 
Nicholas,  335 
Nicholls,  147,  200 
Nicloux,  512 
Nikiforoff,  80 
Nobecourt,  555 
Noble,  165 
Nouguchi,  513 
•  Novy,  154,  376 
Nuttall,  117,  120,  121 


Obermeier,  514 
Oertel,  498>  553 
Ogata,  376,  391 
Ogston,  103 
Okladnych,  373 

Oliver,  49,  71,  141,  165,  173,  177, 

i79>  234 
Opie,  241,  537 
Oppenheim,  533 
Oppenheimer,  534 
Orlowski,  129,  130,  383,  394 
Osier,  275,  291,  293,  332,  382,  391, 

462,  474,  550 
Ossendowski,  533 
Ostrovosky,  438 
Otto,  301 


INDEX  01 


Pacchioni,  502 

Page,  521 

Paine,  518 

Pallowski,  305 

Pappenheim,  188,  195,  304 

Paris,  512 

Park,  391 

Parker,  559 

Patek,  537 

Patella,  520 

Paton,  232 

Pau trier,  511 

Pearce,  497 

Pee,  523,  536 

Peiper,  129,  521 

Penzoldt,  304,  329 

Perry,  254 

Pesel,  547 

Peskind,  170 

Peter,  535 

Peterson,  116 

Petruschky,  526 

Pfahler,  410 

Pfeiffer,  112,  137,  437>  555 

Pick,  557 

Pieraccini,  506 

Pilsbury,  391 

Piorkowski,  532 

Plantenga,  486 

Plehn,  87 

Plimmer,  473 

Poggi,  164,  187 

Pohl,  250 

Poll,  232 

Pollaco,  395 

Pollman,  348 

Ponfick,  185 

Posselt,  329 

Pothier,  559 

Potter,  148,  550 

Powell,  376,  420 

Poynton,  518  . 

Pratt,  414 

Pray,  234 

Price,  441 

Prince,  85 

Prochaska,  506 

Prudden,  154 

Pugh,  495,  497 

Pusey,  331 

Putnam,  488 


Quincke,  279 
Quiserne,  382 


Rabinowitch,  543 
Ranvier,  114,  438 
Rautenberg,  336 


AUTHORS.  5^7 

Reckzeh,  486 
Reed,  D.,  304,  332 
Reed,  W.,  556,  558 
Rees,  376 
Reichert,  161 
Reinert,  410,  493 
Renaud,  486 
Rencki,  477 
Reudiger,  394,  401 
Revenstorf,  104 
Rey,  410 
Reyne,  176 
Reyner,  439 
Ribierre,  435 
Richard,  445 
Richardson,  369,  395 
Richon,  351 
Richter,  238,  412 

Rieder,  231,  232,  234,  247,  258,  316, 

387,  437,  487,  536 
Rigler,  412 
Rindfleisch,  188 
Risel,  379 
Ritchie,  498 
Riviere,  345 
Rodier,  141,  436 
Roger,  113,  254,  391,  557 
Rogers,  373,  378,  391,  440,  442,  443>  471 
Rohnstein,  194 
Rolleston,  291,  347,  349 
Rollet,  170 
Romanowsky,  82 
Romberg,  544 
Roncagliolo,  429 
Rosenberger,  402,  526 
Rosenblath,  379 
Rosenow,  505 
Rosenquist,  191 
Rosin,  162 
Ross,  77,443,445 
Rost,  492 
Rotch,  343,  549 
Row,  377 
Roy,  94 
Ruffner,  473 
Rumpel,  103 
Rumpf,  544 
Rumpff,  129 

Russell,  91,  381,  441,  473 


Sabrazes,  375 
Sailer,  332,  484 
Sambon,  538 
'  Sanarelli,  148,  558 
Sandwith,  440 
Sanfelice,  473 
Sanger,  120 
Sarnow,  515 
Saunby,  381 


[NDEX  OF 


AUTHORS. 


Schafer,  134,  ryo 
Schaffer,  175 
Schaumann,  439 
Schiff,  231,  342 
Schlayer,  391 
Schleip,  537 
Schlesinger,  387 
Schmaltz,  132 
Schmidt,  372,  410 
Schneyer,  388 
Scholz,  395 
Schott,  553 
Schottmuller,  393 
Schreiber,  251 
Schroder,  179 
Schroetter,  178 
Schuffner,  196 
Schultz,  234,  241 
Schultz-Schultzenstein,  129 
Schultze,  205,  438 
Schumberg,  176' 
Schutze,  117 
Schwalbe,  513 
Schwinge,  174 
Scott,  350 
Seemann,  395 
Seligmann,  73,  433 
Sello,  506 
Senator,  329 
Senn,  312,  331 
Sertoli,  506 
Sfameni,  175,  234  ' 
Shaw,  251 

Sherrington,  56,  214,  239,  258,  374 

Shiga,  391,  540 

Shober,  165 

Sicard,  420,  428 

Silvestrini,  506 

Simmons,  332 

Simon,  145,  228,  316 

Singer,  518 

Sippy,  293 

Sittmann,  380,  482,  506,  526 
Slaughter,  414 
Slawyk,  437 
Smith,  J.  C,  559 

Smith,  T.  L.,  122,  125,  139,  267,  276 

Smyth,  494,  495 

Sobotka,  552 

Solimei,  249 

Solley,  81,  513 

Sollmann,  104 

Somers,  495 

Sommerfield,  521 

Sorby,  107 

Sorensen,  174,  490 

Sorochowitsch,  228 

Spencer,  492 

Spezia,  227 

Stadler,  370 


Staehelin,  335 
Stassano,  251 
Steel,  495  ■ 
Steele,  422 
Stefanelli,  544 
Steinberg,  403 
Steinwald,  331 

Stengel,  66,  128,  181,  200,  237,  27:,  354, 

429,502,510,553,555 
Stephens,  469,  470 
Sternberg,  332,  445,  559,  560 
Stevens,  545 
Stewart,  84,  513 
Stintzing,  122,  276 
Stockman,  162 
Stockton,  382 
Stokes,  200 
Stone,  312 
Straus,  372 
Strauss,  129 
Streker,  444 
Strong,  55,  391 
Stump,  537 
Sugg,  555 
Swan,  442,  547 
Symes,  526 


Talley,  429 
Tallquist,  54,  513 
Tassinari,  129 

Taylor,  A.  E.,  258,  307,  308,  321 

Taylor,  F.,  291 

TchlenorfT,  131 

Teichmann,  115,  162 

Thayer,  176,  213,  234,  269,  349,  404, 

445>  455>  466,  482 
Theodor,  351 
Thoma,  57 
Thomas,  131 
Thompson,  554,  556 
Tieken,  103,  335 
Tinker,  103 
Tirelli,  498 
Todd,  538 
Toisson,  56 
Tolot,  481 
Tombleson,  559 
Torday,  544 
Tribondeau,  433 
Triboulet,  148,  518 
Trinkler,  143,  472 
Tschirkoff,  365 
Tschistovitch,  117,  486,  498 
Tucker,  534 
Turner,  433,  481 
Tumas,  551 

Turk,  222,  306,  382,  410,  487,  520 
Tuttle,  482,  490,  506,  527 
Tyson,  333 


INDKX  OK  AUTHORS. 


569 


Uhlkniiuth,  117,  1 20,  1  2  I 
Unger,  394 
Uskow,  224 


Vaillant,  513 
Vaillard,  305 
Valee,  117 
Van  Deen,  116 
Van  den  Berg,  521,  523 
Van  Emden,  287,  298 
Van  Gieson,  438 
Van  Niessen,  532 
Vaquez,  435 

Vasquez,  334,  335.  3§2>  420 

Vast,  513 

Vaughan,  154 

Vermehren,  149 

Viault,  178 

Vicarelli,  181 

Vincent,  437 

Von  Bockmann,  516 

Von  Fleischl,  43 

Von  Gebhardt,  544 

Von  Jaksch,  129,  131,  143.  J4S»  l67»  251. 
259>  277.  354,  413,  425.  49°.  498,  5°9. 

512 

Von  Lerber,  248 

Von  Limbeck,  106,  129,  177,  181,  209, 
232,  242,  250,  268,  277,  287,  297,  316, 
410,  413,  431*  435.  49°.  498.  515 

VonNoorden,  189,  194,  256,  374 

Von  Seiller,  164 

Vorbach,  426 

Vomer,  535 

Vulpius,  334 


Weigert,  112 

Weil,  322,  3S0,  555,  557 

Weil,  E.,  258,  433 

Weinberger,  379 

Weiss,  208,  226 

Welch,  109,  153,  154,  5 26 

Wellman,  493 

Wende,  329 

Wentworth,  231 

Wey,  304 

Wherry,  496 

White,  C.  Y.,  244,  354,  5°2.  5IO>  555 

White,  F.  K.,  233,  49°>  5o6>  527 

White,  W.  H.,  142 

Whitney,  231 

Whittier,  121 

Widal,  113,  398,  555 

Widowitz,  522 

Wilkinson,  251,  254 

Willebrand,  176,  234 

Williams,  487 

Williamson,  96,  263,  347,  383 
Wilson,  J.C,  509 
Wilson,  L.  B.,  531 
Winiarski,  444 
Winter,  405 

Winternitz,  176,  234,  250,  261 
Wolff,  178,  226 
Wolff,  A.  J.,  402 
Wood,  438 

Wright,  A.  E.,  96,  101,  239,  393,  428, 

484.  544 
Wright,  J.  H.,  82,  442 
Wuntz,  420 
Wyss,  512 


Yarrow,  512 
Yersin,  376 
Young,  366 


Waele,  555 

Wagner,  233 

Waldstein,  78,  290 

Waldvogel,  278 

Walker,  148,  5 18 

Walz,  304 

Wanstall,  502 

Warfield,  230,  390,  394 

Warren,  334 

Warthin,  172 

Wasielewski,  556 

Wassermann,  117,  154,  370,  518 

Watson,  426 

Weber,  485,  556 

Weber,  C.  H.,  312 

Weber,  F.  B.,  290,  493 

Wegefarth,  200 


Zadoc,  518 
Zahorsky,  390 
Zammit,  484 
Zandy,  251 
Zangmeister,  233,  341 
Zappert,  60,  256,  498,  523 
Zeri,  199,  47 1 
Ziemke,  121 
Zinno,  378 
Zlatogoroff,  485 
Zollikofer,  226 
Zuntz,  129,  176,  178 
Zypkin,  292 


INDEX  OF  SUBJECTS. 


Abscess,  361 

appendicular,  368 
cerebral,  488,  493 
coagulation,  361 
Color  index,  361 
diagnosis,  363 
erythrocytes,  361 
fibrin,  361 

gall-bladder,  363,  370,  380 

hemoglobin,  361 

hepatic,  363,  391 

iodophilia,  361 

leucocytes,  362 

normoblasts,  362 

ovarian,  370 

pancreatic,  499 

pelvic,  363  _ 

perinephritic,  370 

pleural,  504 

pulmonary,  363 

renal,  363 

superficial,  363 

tonsillar,  536 

tuberculous,  546,  548 
Absence  of  leucocytosis,  262 

in  acute  infections,  262 
in  chlorosis,  272 
in  enteric  fever,  406 
in  helminthiasis,  440 
in  influenza,  436 
in  kala-azar,  443 
in  leprosy,  444 
in  malarial  fever,  469 
in  Malta  fever,  484 
in  measles,  485 
in  paratyphoid  fever,  262 
in  pernicious  anemia,  285 
in  rotheln,  486 
in  serous  pleurisy,  503 
in  splenic  anemia,  292 
in  trypanosomiasis,  541 
in  tuberculosis,  547 
in  typhus  fever,  551 
in  yellow  fever,  560 
significance  of,  240 
Acetanilid  poisoning,  5 1 1 
Acetone,  test  for,  145 
Acetonemia,  145 
Achroiocythemia,  163 


Achromacytes,  185 
Acid  dyes,  76 

Acidity  of  blood  in  Asiatic  cholera,  372 

in  insolation,  438 
Acromegaly,  364 
Actinomycosis,  364 
Acute  yellow  atrophy  of  the  liver,  365 
Addison's  disease,  365 
Adenitis,  254,  331 
Afanassiew's  bacillus,  515 
Agglutinins,  156 
Agglutinoids,  157 
Ague  cake,  338 
Akatama,  493 
Albuminuria,  135 
Alcohol  and  ether  fixation,  80 

fixation,  80 

poisoning,  511 
Alcoholic  neuritis,  492 
Alcoholism,  511 
Alexins,  238 

in  relapsing  fever,  5 1 7 
Alkalimeter,  Engel's,  96 
Alkalinity,  96,  128 

estimation  of,  96 

in  Asiatic  cholera,  372 

in  chlorosis,  268 

in  diabetes  mellitus,  383 

in  epilepsy,  497 

in  erysipelas,  410 

in  fever,  412 

in  gastric  carcinoma,  472 
in  gout,  426 

in  hemorrhagic  diseases,  428 
in  Hodgkin's  disease,  327 
in  icterus,  344 

in  infantile  enteric  fever,  354 
in  insolation,  438 
in  lymphatic  leukemia,  317 
in  mental  diseases,  496  _ 
in  myelogenous  leukemia,  307 
in  nephritis,  490 
in  osteomalacia,  499 
in  pernicious  anemia,  278 
in  rheumatic  fever,  518 
in  scurvy,  428 
in  secondary  anemia,  296 
in  uremia,  490 
I  Altitude,  effect  on  blood,  178 


57i 


572 


INDEX  OF  SUBJECTS. 


Altmann's  bioblastic  theory,  208 
Amboceptor,  154 
Amebic  dysentery,  391 
Amebula,  449 
Ammonia  poisoning,  512 
Amphophile  granules,  207 
Amyl  nitrite  poisoning,  5 1  r 
Amyloid  disease,  482 
Analysis,  centrifugal,  91 
Anemia,  148 

angiospastic  pseudo-,  149 
bothriocephalus,  439 
brick-makers',  440 
classification  of,  150 
edema  of,  489 
following  splenectomy,  233 
from  ankylostomiasis,  438 
from  Ascaris  lumbricoides,  438 

from  gastric  tubule  atrophy,  422 

from  helminthiasis,  438 

from  threadworms,  438 

from  thyroidization,  489 

in  Addison's  disease,  365 

in  appendicitis,  366 

in  carcinoma,  473 

in  children,  345 

in  gastric  carcinoma,  474 

in  hemorrhagic  diseases,  479 

in  hepatic  cirrhosis,  430 

in  icterus,  435 

in  kala-azar,  443 

in  malignant  disease,  273,  478 
endocarditis,  482 

in  nephritis,  490 

in  rheumatic  fever,  519 

in  sarcoma,  478 

in  sepsis,  527 

in  syphilis,  532 

in  trypanosomiasis,  541 

in  tuberculosis,  544 

in  typhus  fever,  551 

in  variola,  556 

in  yellow  fever,  559 

infantum  pseudo-leukemica,  354 

miners',  440 

pathogenesis,  151 

pernicious,  276 

post-hemorrhagic,  299 

post-malarial,  466 

post-typhoid,  404 

primary,  150 

pseudo-,  149 

secondary,  296 

splenic,  291 

syphilitic,  533 

toxic,  511 

tropical,  149 

Von  Jaksch's,  354 
Anemias  of  infancy  and  childhood,  341 
bacteriemia,  356 
classification,  346 


Anemias  of    infancy  and  childhood, 
erythroblasts,  345 
frequency,  345 
gastro-intestinal,  353 
general  characteristics, 
345 

leukemia,  348 
megaloblasts,  345 
mild,  351 
pernicious,  347 
post-typhoid,  354 
primary,  347 
rachitic,  353 
secondary,  351 
severe,  531 
splenic,  347 

splenic  enlargement,  346 

syphilitic,  352 

tuberculous,  353 

with  leucocytosis,  352 
Aneurism,  363 
Anhydremia,  140 
Anilin  dyes,  76 
Anisocytosis,  182 
Ankylostomiasis  anemia,  438 
Anopheles,  415,  447 
Anthrax,  366 
Antipyrin  poisoning,  512 
Antiamboceptors,  155 
Antibodies,  153 
Anticomplements,  155 
Antihemolysis,  155 

Antipyretics,  effect  on  erythrocytes,  166 

leucocytes,  510 
Antisera,  117 
Antitoxin,  153 
Aortic  lesions,  447 
Apoplectiform  attacks,  495 
Appendicitis,  366 

anemia,  366 

diagnosis,  370 

iodophilia,  370 

leucocytosis,  368 
Arloing  and  Courmont's  reaction,  542 
Arsenic,  effect  on  blood,  163 

effect  on  trypanosomata,  539 
Arseniuretted  hydrogen  poisoning,  512 
Arthritis  deformans,  371 

gonorrheal,  521 

septic,  525 
Ascaris  lumbricoides,  438 
Ascites,  431 

chylous,  421 

effect  on  blood,  431 
Asiatic  cholera,  372 
Aspidium  poisoning,  512 
Asthma,  374 

Atmospheric  cold,  effect  on  blood,  234 
Atrophic  hepatic  cirrhosis,  430 
Atypical  erythroblasts,  192 
Autolysis,  154 


INDEX  OF  SUBJECTS. 


573 


Bactericidal  action  of  blood,  130,  238 
Bacteriemia,  146 

in  acute  mania,  496 
in  anthrax,  366 
in  bcri-bcri,  492 
in  bubonic  plague,  376 
in  cerebro-spinal  fever,  488 
in  cholelithiasis,  380 
in  enteric  fever,  393 
in  epilepsy,  497 
in  glanders,  425 
in  hepatic  cirrhosis,  432 
in  infants,  356 
in  influenza,  436 
in  gonorrheal  infection,  426 
in  leprosy,  444 
in  leukemia,  305 
in  malignant  disease,  473 
in  malignant  endocarditis,  482 
in  Malta  fever,  484 
in  measles,  485 
in  meningitis,  488 
in  nephritis,  490 
in  paratyphoid  fever,  395 
in  pneumonia,  505 
in  purpura,  428 
in  relapsing  fever,  514 
in  rheumatic  fever,  518 
in  scarlet  fever,  521 
in  scurvy,  427 
in  sepsis,  526 
in  syphilis,  532 
in  tuberculosis,  542 
in  typhus  fever,  550 
in  variola,  555 
in  yellow  fever,  559 
Bacteriological  examination,  109 
Banti's  disease,  294 
Barlow's  disease,  427 
Basedow's  disease,  411 
Basic  dyes,  76 
Basophile  granules,  207 
Basophiles,  217.   See  Mast  Cells. 
Basophilia,  258 
granular,  194 
perinuclear,  228 
Baths,  effect  on  blood,  176 
Benario's  method,  81 
Beri-beri,  492 
Biermer's  disease,  276 
Bile  in  the  blood,  145 

test  for,  145 
Bilharziasis,  441 
Biliary  colic,  381 
Bioblastic  theory,  Altmann's,  208 
Blackwater  fever,  470 
Blastomycetes  in  carcinoma,  473 

in  tuberculosis,  542 
Bleeders,  35 

Blood,  arterial  and  venous,  126 


Blood  at  birth,  342 

bactericidal  action,  130,  238 

biological  test,  j  i  7 

carbonic  acid,  126 

color,  126 

concentration,  197 

crisis,  189 

cryoscopy,  102 

crystals,  161 

cultures,  109,  147 

dust,  200 

extractives,  126 

fats,  126 

fetal,  341 

filaria,  413 

films,  methods  of  preparing,  76 
freezing  point,  103 
gases,  126 

general  composition,  125 
laked,  127 
lancet,  34 
lytic  action,  154 
medico-legal  tests,  114 
odor,  127 
oxygen,  126 
parasites,  39 
Blood  plaques,  198 

counting  the,  90 

Ducchesi's  method  of  demon- 
strating, 199 

in  bubonic  plague,  378 

in  burns,  378 

in  chlorosis,  274 

in  diabetes  mellitus,  386 

in  enteric  fever,  409 

in  erysipelas,  410 

in  hemorrhagic  diseases,  430 

in  Hodgkin's  disease,  330 

in  kala-azar,  443 

in  lymphatic  leukemia,  321 

in  malarial  fever,  471 

in  measles,  485 

in  myelogenous  leukemia,  317 
in  pernicious  anemia,  287 
in  pneumonia,  510 
in  post-hemorrhagic  anemia, 
301 

in  scarlet  fever,  524 
in  secondary  anemia,  29S 
in  splenic  anemia,  293 
in  syphilis,  535 
in  variola,  557 
nature,  199 
normal  number,  200 
pathological  variations,  200 
plasma,  125 

plasmotropic  action,  439 
proteids,  125 
quantity,  125 
)  quotient,  165 


574  index  or 

Blood,  reaction,  128 
regeneration,  301 

after  splenectomy,  333 
after  surgical  operations,  473 
after  the  Schott  treatment,  533 
after  treatment  with  iron  and 

arsenic,  163 
after  treatment  with  mercury, 
533 

after  treatment  with  supra- 
renal extract,  366 
in  anemias  of  children,  346 
in  bothriocephalus  anemia,  290 
in  carcinoma,  473 
in  diphtheria,  386 
in  enteric  fever,  404 
in  malarial  fever,  468 
in  pernicious  anemia,  280 
in  post-hemorrhagic  anemia, 

in  scarlet  fever,  523 
in  syphilis,  533 
in  tuberculosis,  546 
in  variola,  556 
salts,  126 
serum,  125 
specific  test  for,  117 
spectra,  168 
viscosity,  127 
viscosity  value,  128 
Bodies,  Leishman-Donovan,  442 
Bone  marrow,  171 

in  leucocytosis,  241 
in  malignant  disease,  480 
Bordet's  reaction,  117 
Bothriocephalus  anemia,  439 
Brain,  abscess,  363 
hemorrhage,  493 
tumor,  493 
Bra's  neurococcus,  497 
Breast,  carcinoma  of,  476 
Bremer's  test,  384 
Bright's  disease,  489 
Bromin  poisoning,  512 
Bronchitis,  375 
Bubonic  plague,  376 
Budding  of  protoplasm  of  lymphocytes, 
320 

Bullet  wounds,  effect  on  blood,  252 
Burns,  378 


Cachexia,  malarial,  468 
Calcium  salts,  effect  on  blood,  134 
Capillary  bronchitis,  508 
Carbon  monoxid  hemoglobin,  168 

poisoning,  512 

spectrum,  168 

test  for,  169 
Carbuncle,  244 


SUBJECTS. 

Carcinoma,  472 

alkalinity,  472 

coagulation,  472 

color  index,  473 

deformed  erythrocytes,  475 

diagnosis,  480 

digestion  leucocytosis,  477 

erythroblasts,  475 

erythrocytes,  473 

esophageal,  477 

fibrin,  472 

gastric,  474,  477 

hemoglobin,  473 

hepatic,  476 

intestinal,  476 

leucocytes,  475 

lingual,  477 

mammary,  476 

metastases,  475,  480 

pancreatic,  476 

polycythemia,  474 

protozoa,  473 

pulmonary,  505 

rectal,  476 

regeneration,  473 

renal,  476 

specific  gravity,  472 

sugar,  472 

uterine,  476 
Castration,  effect  on  blood,  258 
Catarrhal  pneumonia,  508 
Cecum,  malignant  disease,  370 
Cellular  elements  of  blood,  125 

plethora,  139 
Centrifugal  analysis,  91 
Cerebro-spinal  meningitis,  487 
Charcot-Leyden  crystals  in  leukemia, 
3°7. 

Chemical  fixation,  80 
Chemotaxis,  237 
Chicken-pox,  554 
Chloral  poisoning,  512 
Chloro-anemia,  270 
Chloroform  narcosis,  249 
Chloroma,  379 
Chlorosis,  267 

alkalinity,  268 

appearance  of  fresh  blood,  267 
blood  plaques,  274 
blood  volume,  267 
coagulation,  268 
color  index,  269. 
diagnosis,  274 
dry  residue,  267 
Egyptian,  440 
eosinophiles,  273 
erythroblasts,  271 
erythrocytes,  269 
florida,  275 

granular  basophilia,  271 


INDEX  OF  SUBJECTS. 


575 


Chlorosis,  hemoglobin,  269 
heredity,  275 
leucocytes,  272 
male,  275 
microcytosis,  270 
myelocytes,  274 
oxygen  capacity,  267 
pallor  of  erythrocytes,  271 
poikilocytosis,  271 
polychromatophilia,  27 1 
polynuclear  neutrophils,  272 
pseudo-,  149 

relative  lymphocytosis,  272 
sex,  275 

specific  gravity,  268 
symptoms,  275 
syphilitic,  532 
transitional  forms,  272 
without  blood  changes,  274 

Cholangitis,  381 

Cholecystitis,  381 

Cholelithiasis,  380 

Cholemia,  145 

Cholera,  Asiatic,  372 

Chorea,  498 

Chromic  acid  fixation,  81 

poisoning,  512 
Chyluria,  parasitic,  421 
Cirrhosis  of  the  liver,  430 
Clap,  426 

Class'  diplococcus,  521 
Coagulation,  134.    See  Fibrin. 
in  abscess,  361 
in  acromegaly,  364 

in  albuminuria,  135 

in  bubonic  plague,  376 

in  carcinoma,  472 

in  chlorosis,  268 

in  cholelithiasis,  380 

in  cobra  poisoning,  134 

in  cyanosis,  382 

in  daboia  poisoning,  134 

in  eclampsia,  135 

in  enteric  fever,  393 

in  fever,  412 

in  hemophilia,  428 

in  hemorrhagic  diseases,  428 

in  Hodgkin's  disease,  327 

in  icterus,  434 

in  infantile  enteric  fever,  354 

in  lymphatic  leukemia,  317 

in  myelogenous  leukemia,  307 

in  nephritis,  490 

in  obstructive  jaundice,  434 

in  pernicious  anemia,  278 

in  pneumonia,  505 

in  pregnancy,  135 

in  rheumatic  fever,  518 

in  sarcoma,  478 

in  scarlet  fever,  521 


Coagulation  in  scurvy,  428 
in  secondary  anemia,  296 
in  snake  poisoning,  513 
in  splenic  anemia,  291 
in  yellow  fever,  558 
relation  to  intestinal  hemorrhage, 

393 

time,  estimation  of,  100 
Coagulometer,  Wright's,  101 
Cobra  poisoning,  134 
Colic,  biliary,  381 
Color  index,  165 

of  the  blood,  126 

in  anilin  poisoning,  127 
in  carbon  monoxid  poisoning, 
168 

in  chlorosis,  267 
in  cyanosis,  382 
in  diabetes  mellitus,  383 
in  dyspnea,  127 
in  Hodgkin's  disease,  327 
in  hydrocyanic  acid  poisoning, 
127 

in  icterus,  434 
in  lymphatic  leukemia,  317 
in  myelogenous  leukemia,  306 
•in  nitrobenzene  poisoning,  127 
in  pernicious  anemia,  277 
in  potassium  chlorate  poison- 
ing, 127 
in  secondary  anemia,  296 
in  splenic  anemia,  291 
in  sulphuretted  hydrogen  poi- 
soning, 127 
normal  variations,  126 
pathological  variations,  127 
Coma,  diabetic,  383 
Complement,  154 
Complementophiles,  155 
Concentration  of  the  blood,  197 
Constitutio  lymphatica,  254 
Contusions,  effect  on  blood,  252 
Convulsions,  495 
Corpuscles,  Eichhorst's,  183 
phantom,  184 
Poggi's,  185 
Ponfick's,  184 
Corrosive  metallic  salts,  poisoning  by, 

512 

Counting  chamber,  Thoma-Zeiss,  58 
Zappert,  59 

differential,  89 

dry  film  method,  73 

the  blood  plaques,  90 

the  erythrocytes,  60,  69,  71,  72,  74 

the  leucocytes,  64,  69,  71,  74 
Cover-glasses,  cleaning  the,  36 
Coxalgia,  346,  348 
Crenation,  169,  465 
Crisis,  blood,  189 


5  76  INDEX  OF  SUBJECTS. 


Cryoscope,  Fontaine's,  104 
Cryosco})y,  102 

Crystals,  Charcot-Leydcn,  307 

hematoidin,  162 

oxyhemoglobin,  ]  61 

Teichmann's,  162 
Culex  fatigans,  382,  415,  447 
Cultures,  blood,  109,  147 
Cyanosis,  effect  on  blood,  381,  553 
Cyanotic  polycythemia,  381 
Cyst,  ovarian,  303 

pancreatic,  499 
Cystitis,  189 
Cytophiles,  155 
Cytoryctes  variolar,  556 


Daboia  poisoning,  134 
D  aland' s  hematocrit,  91 
Dare's  hemo-alkalimeter,  98 

hemoglobinometer,  40 
Degeneration,  endoglobular,  184 
Delafield's  hematoxylin,  87 
Delhi  sore,  442 
Delirium,  495 
Dementia,  495 
Dengue,  382 
Denige's  solution,  145 
Density  and  opacity  of  blood,  126 
Dermacentor  reticulatus,  531 
Dermatitis  herpetiformis,  256 
Diabetes  mellitus,  383 

alkalinity,  383 

blood  plaques,  386 

Bremer's  test,  384 

diagnosis,  386 

erythrocytes,  385 

glycemia,  383 

hemoglobin,  385 

iodophilia,  226 

leucocytes,  386 

lipacidemia,  383 

lipemia,  383 

specific  gravity,  385 

Williamson's  test,  383 
Diapedesis,  207 
Diaphragm,  ocular,  65 
Diarrhea,  390 
Differential  counting,  89 
table  of  anemias,  303 

of  gastric  cancer  and  ulcer,  481 

of  leucocytosis,  lymphocytosis, 
and  leukemia,  337 

of  malignant  disease  and  per- 
nicious anemia,  480 

of  normoblasts  and  megalo- 
blasts,  191 

of  the  leucocytes,  223 

of  the  malarial  parasites,  463 


Digestion  leucocytosis,  231 

in  diabetes  mellitus,  386 
in  gastric  carcinoma,  477 
in  gastric  ulcer,  424 
in  gastritis,  423 
in  infants,  344 

Digestive  lymph  wave,  177 

Dilatation  of  stomach,  422 

Diluting  fluids,  56 

Diphtheria,  386 
diagnosis,  390 

effects  of  antitoxin,  386,  388 

eosinophilia,  389 

erythrocytes,  386 

hemoglobin,  386 

leucocytes,  387 
Disease,  Addison's,  365 

Banti's,  294 

Barlow's,  427 

Basedow's,  411 

Biermer's,  276 

Bright's,  489 

Duhring's,  256 

Graves',  411 

Griesinger's,  440 

Hodgkin's,  327 

hydatid,  433 

Laennec's,  431 

malignant,  472 

Neisser's,  426 

Osier's,  381 

Pott's,  546,  548 

Still's,  326 

Von  Jaksch's,  354 

Werlhoff's,  429 
Diseases,  hemorrhagic,  427 
Drowning,  freezing  point  of  blood,  104 
Drug  eosinophilia,  257 

leucocytosis,  249 

leucopenia,  262 

lymphocytosis,  254 
Duodenal  ulcer,  425 
Durham's  hemocytometer,  68 
Dwarf  myelocytes,  222 
Dyes,  anilin,  76 
Dysentery,  391 


Echinococcus,  433 
Ectopic  pregnancy,  370,  502 
Eczema,  256 
Edema  of  anemia,  489 
Effusion,  pericardial,  500 

peritoneal,  500 

pleural,  503 
Egyptian  chlorosis,  440 
Ehrlich's  hypothesis,  208 

side-chain  theory,  151 

triacid  stain,  83 
Ehrlich-Weigert  fluid,  112 


IN  1)10 X  OF  SUBJECTS. 


577 


Eichhorst's  corpuscles,  183 
Electricity,  effect  on  blood,  234 
Elephantiasis  Arabum,  421 
Emphysema,  374 
Empyema  of  gall-bladder,  380 

of  thorax,  504 
Endocarditis,  malignant,  482 
Endoglobular  degeneration,  184 
Engel's  alkalimeter,  96 
Enteralgia,  371 
Enteric  fever,  393 

bacteriology,  393 

coagulation,  393 

diagnosis,  409 

erythrocytes,  404 

Ficker-Reudiger  test,  401 

hemoglobin,  404 

leucocytes,  406 

serum  test,  396 

spot  cultures,  395 

Wolff's  test,  402 
Enteritis,  390 

Eosin  and  hematoxylin  stain,  87 
and  methylene-blue  stain,  86 
Eosinophile  granules,  208 
Eosinophiles,  216 

diminution  of,  after  castration,  258 

after  hemorrhage,  258 

during  digestion,  257 

in  acute  febrile  diseases,  258 

in  bubonic  plague,  378 

in  carcinoma,  478 

in  chlorosis,  273 

in  diphtheria,  389 

in  enteric  fever,  409 

in  erysipelas,  411 

in  gastric  ulcer,  425 

in  Hodgkin's  disease,  330 

in  hydatid  disease,  433 

in  influenza,  257 

in  lymphatic  leukemia,  320 

in  malarial  fever,  471 

in  measles,  486 

in  meningitis,  488 

in  pernicious  anemia,  286 

in  pertussis,  502 

in  phthisis,  547 

in  pneumonia,  510 

in  sarcoma,  480 

in  sepsis,  529 

in  varicella,  555 

physiological,  257 

terminal,  257 
Eosinophilia,  255 
after  coitus,  256 
after  splenectomy,  336 
definition,  255 
during  menstruation,  256 
experimental,  257 
factors,  255 


Eosinophilia,  in  ankylostomiasis,  440 

in  asthma,  375 

in  bilharziasis,  441 

in  chloroma,  379 

in  chorea,  498 

in  diseases  of  the  bones,  256 
of  the  sexual  organs,  257 
of   the   sympathetic  nervous 
system,  257 

in  filariasis,  420 

in  gonorrhea,  426 

in  guinea-worm  infection,  420 

in  helminthiasis,  440 

in  hemorrhagic  effusions,  503 

in  herpes  zoster,  434 

in  hydatid  disease,  433 

in  hysteria,  494 

in  infancy,  344 

in  kala-azar,  443 

in  myelogenous  leukemia,  315 

in  osteosarcoma,  480 

in  oxyuris  vermicularis  infection, 
440 

in  paresis,  495 
in  rheumatic  fever,  520 
in  scarlet  fever,  524 
in  septicemia,  529 
in  skin  diseases,  256 
in  splenic  tumors,  257 
in  starvation,  257 
in  syphilis,  535 

in  Taenia  mediocanellata  infection, 
440 

in  trichiniasis,  536 

in  variola,  557 

in  xanthin  diatheses,  257 

physiological,  257 

post-febrile,  257 
Eosinophilic  myelocytes,  219 
Epilepsy,  497 
Erysipelas,  410 
Erythroblasts,  187 

atypical  forms,  192 

differential  count  of,  89 
Erythrocytes,  169 

after  fasting,  176 

ameboid  motility,  180 

appearance  in  fresh  blood,  169 

atypical  staining,  186 

averages  in  anemia,  197 

color,  169 

counting  the,  60,  68,  70,  72,  73 
crenation,  169 

deformities  of  size  and  shape,  182 

destruction,  171 

development,  171 

dry  film  method  of  counting,  73 

endoglobular  degeneration,  184 

granular  basophilia,  194 

histological  structure,  170 


37 


578 


INDEX  OF  SUBJECTS. 


Erythrocytes,  hyperviscosity,  i8t 
influence  of  age  and  sex,  174 
of  climate,  1 80 

of  constitution  and  nutrition, 
176 

of  digestion,  177 
of  fatigue,  176 
of  high  altitudes,  178 
of  muscular  exercise,  176 
of  physical  factors,  174 
of  pregnancy,  menstruation, 
and  lactation,  175 
isotonicity,  180 
methods  of  counting,  55 
monochromatophilia,  186 
necrosis,  185 
normal  number,  209 
nucleation,  187 
origin  and  life  history,  171 
oval -shaped,  115,  184 
pathological'changes,  18c 
physiological  changes,  174 
polychromatophilia,  186 
resistance,  106 
rouleaux  formation,  169 
shape,  169 
size,  172. 
stroma,  170 
volume,  173 
Erythrocytometer,  57 
Erythromelalgia,  493 
Erythropyknosis,  459 
Estimation  of  alkalinity,  96 
of  coagulation  time,  100 

glass  slide  method,  100 
Wright's  method,  101 
of  hemoglobin  percentage,  39 
of  resistance  of  erythrocytes,  106 
of  specific  gravity,  94 
of    volume    of    corpuscles  and 
plasma,  91 
Ether  leucocytosis,  248 

narcosis,  512 
Examination  of  the  stained  specimen,  75 

of  the  unstained  specimen,  33 
Exercise,  effect  on  blood,  176 
Exophthalmic  goiter,  411 
Experimental  eosinophilia,  257 
leucocytosis,  249 
lymphocytosis,  254 
Extractives  of  blood,  94 


Family  periodic  paralysis,  497 
Fat  in  the  blood,  141 

tests  for,  142 
Fatty  acids  in  the  blood,  145 

test  for,  146 
Felon,  244 
Fetal  blood,  341 


Fever,  dum-dum,  539 
effect  on  blood,  41  j 
enteric,  393 
gastric,  421 
malarial,  445 
Malta,  484 
paratyphoid,  394,  404 
puerperal,  529 
relapsing,  514 
rheumatic,  518 
scarlet,  521 

spotted  (Montana),  53  l 
spotted  (typhus),  550 
thermic,  437 
tick,  531 

trypanosoma,  539 
typhus,  550 
yellow,  558 
Fibrin,  134.    See  Coagulation. 
in  abscess,  361 
in  acromegaly,  364 
in  carcinoma,  472 
in  chlorosis,  268 
in  cholelithiasis,  380 
in  erysipelas,  410 
in  fever,  412 
in  gout,  426 

in  Hodgkin's  disease,  327 
in  influenza,  437 
in  lymphatic  leukemia,  317 
in  measles,  485 

in  myelogenous  leukemia,  307 

in  nephritis,  490 

in  pernicious  anemia,  278 

in  pneumonia,  505 

in  rheumatic  fever,  518 

in  sarcoma,  478 

in  scarlet  fever,  521 

in  sepsis,  525 

in  splenic  anemia,  291 

in  variola,  555 

in  yellow  fever,  558 

pathological  variations,  136 

relation  to  leucocytosis,  137 
Filariasis,  413 

diagnosis,  421 

erythrocytes,  419 

Filaria  nucturna,  414 

hemoglobin,  419 

leucocytes,  420 

occurrence,  413 

parasitology,  413 
Films,  preparing  the,  76 

staining  the,  81 
Fixation  methods,  79 
chemical,  80 
heat,  79 
Floating  kidney,  371 
Fluids,  diluting,  56 
Fluorescence  of  quinin,  446 


INDEX  OF  SUBJECTS. 


579 


Fontaine's  cryoscopc,  104 
Formalin  fixation,  81 
Fractures,  421 
Freezing  point  of  blood,  102 
Fresh  blood,  microscopical  examination 
of,  33 

Functional  neuroses,  493 

Furuncle,  244 

Fusel  oil  poisoning,  512 


Gall-stone,  380 
Gametes,  446 
Gangrene,  244 

appendicular,  369 
Garrod's  thread  test,  144 
Gases  of  blood,  126 
Gastrectasis,  422 
Gastric  achylia,  422 

carcinoma,  476,  481 

dilatation,  422 

neurasthenia,  422 

tubule  atrophy,  422 

ulcer,  423 
Gastritis,  421 
Gastro-enteritis,  390 
Gastroptosis,  422 
Gelatin,  effect  on  blood,  134 
Genito-urinary  tuberculosis,  546,  549 
German  measles,  486 
Glanders,  425 
Globuli  rossi  attonati,  468 
Globulin,  171 
Glossina  palpalis,  539 
Glycemia,  143 

after  pancreatectomy,  143 

in  carcinoma,  472 

in  diabetes  mellitus,  383 
Goiter,  exophthalmic,  411 
Goldhorn's  stain,  88 
Gonorrhea,  426 
Gonorrheal  arthritis,  521 
Gout,  426 

Gowers'  hemocytometer,  69 
hemoglobinometer,  52 

Granular  basophilia,  194 

in  carcinoma,  475 

in  lead  poisoning,  196 

in  lymphatic  leukemia,  195 

in  malarial  fever,  468 

in  myelogenous  leukemia,  310 

in  pernicious  anemia,  285 

in  secondary  anemia,  297 

in  sepsis,  528 

in  tropical  anemia,  195 

Granules,  leucocyte,  207 
Neusser's,  228 
Schuffner's,  196 

Graves'  disease,  411 

Grippe,  436 


Guaiacol  poisoning,  512 
Guinea  worm,  420 
Gumma,  363 
Giinther's  method,  112 


Haig's  blood  decimal  card,  55 
Haldane's  hemoglobinometer,  53 
Halitus  of  blood,  127 
Hamburger's  method,  106 
Hammerschlag's  method,  94 
Hanging-drop  test,  122 
Haptins,  153 
Haptophores,  152 
Flay  em's  achromacytes,  185 
pseudo-bacilli,  183 
solution,  56 
Heart,  chronic  valvular  disease,  552 
dilatation,  500 
ulcerative  endocarditis,  482 
Heat  exhaustion,  437 

fixation,  79 
Helminthiasis,  intestinal,  438 
Helminthoma  elastica,  421 
Hemamceba  leukemia?,  305 

malarise,  445 
Hematin,  162 
Hematoidin,  162 
Hematokrit,  Daland's,  91 
Hematoma,  363 
Hematoporphyrin,  162 
Hematoxylin,  Delafield's,  87 
Hematuria,  malarial,  470 
Hemin,  162 

Teichmann's  test,  115 
Hemo-alkalimeter,  Dare's,  98 
Hemochromogen,  161 
Hemocytolysis,  151,  153,  511 
in  ankylostomiasis,  439 
in  aspidium  poisoning,  512 
in  fever,  412 

in  fusel  oil  poisoning,  512 

in  guaiacol  poisoning,  512 

in  insolation,  438 

in  malarial  fever,  467 

in  pyrodin  poisoning,  513 

in  toluylendiamin  poisoning,  313 

in  yellow  fever,  559 
Hemocytometer,  Durham's,  68 

Gowers',  69 

Oliver's,  71 

Thoma-Zeiss,  57 
Hemogenesis,  171 

adult,  188 

deficient,  151 

embryonal,  190 
Hemoglobin,  161 

absolute  amount,  165 

after  anesthesia,  249 
averages  in  anemia,  164 


5»c 


INDEX  OF  SUBJECTS. 


Hemoglobin,  carbon  monoxid,  168 
chemistry  of,  1 61 
during  menstruation,  164,  175 
estimation  of,  40,  43,  49,  52,  54 
influence  of  arsenic  on,  163 
of  iron  on,  163 

of  mercury  and  iodids  on,  533 
origin,  162 
reduced,  161 

tests  in  surgical  operations,  164 
Hemoglobinemia,  166 

from  burns,  166 

from  drugs,  166 

from  exposure  to  cold,  166 

from  heterogeneous  blood  trans- 
fusion, 166 

in  acute  yellow  atrophy  of  the  liver, 
365 

in  enteric  fever,  124 

in  epidemic  hemoglobinuria,  167 

in  insolation,  '438 
.  in  malarial  fever,  467 

in  paroxysmal  hemoglobinuria,  167 

in  poisoning,  511 

in  Raynaud's  disease,  167 

in  scarlet  fever,  523 

in  scurvy,  167 

in  sepsis,  528 

in  syphilis,  533 

in  typhus  fever,  551 

in  variola,  556 

in  Winckel's  disease,  154 

in  yellow  fever,  559 

spectrum  of,  168 

test  for,  167 
Hemoglobinometer,  Dare's,  40 

Gowers',  52 

Haldane's,  53 

Oliver's,  49 

Tallquist's,  54 
Hemokonia,  200,  466 
Hemolymph  glands,  225 
Hemolysis,  151.    See  Hemocytolysis. 
Hemometer,  von  Fleischl's,  43 
Hemophilia,  427 

Hemophilics,  danger  of  hemorrhage  in, 
35 

Hemorrhage,  cerebral,  493 

effect  on  blood,  299 

gastric,  423 

intestinal,  408 

pancreatic,  499 

post-operative,  245,  336 

pulmonary,  545,  547 

regeneration  after,  301 

renal,  470,  490 

treatment  by  transfusion,  301 
Hemorrhagic  diseases,  427 
Hepatic  abscess,  363 

carcinoma,  476 


Hepatic  cirrhosis,  430 

colic,  381 
Herpes  zoster,  434 
Hewes'  stain,  85 
Hodgkin's  disease,  327 
alkalinity,  327 

appearance  of  fresh  blood,  327 
basophiles,  330 
blood  plaques,  330 
coagulation,  327 
color  index,  328 
deformed  erythrocytes,  328 
diagnosis,  330 
eosinophiles,  330 
erythroblasts,  328 
erythrocytes,  327 
hemoglobin,  327 
influence  of  x-rays,  331 
leucocytes,  328 
mast  cells,  330 
myelocytes,  330 
polychromatophilia,  328 
poly  nuclear  neutrophiles,  329 
relative  lymphocytosis,  328 
specific  gravity,  327 
symptoms,  331 

transformation  into  lymphatic 
leukemia,  329 
Hydatid  disease,  433 
Hydremia,  139 

in  fever,  412 

in  nephritis,  489 

in  valvular  heart  disease,  553 

in  yellow  fever,  559 
Hydrocyanic  acid  poisoning,  512 
Hydroperitoneum,  431 
Hydrophobia,  513 
Hyperchlorhydria,  422 
Hyperinosis,  135 
Hyperleucocytosis,  239 
Hyperplasia,  lymphatic,  327 
Hypertonicity,  180 
Hypertrophic  hepatic  cirrhosis,  431 
Hyperviscosity,  181 
Hypinosis,  135 
Hypochlorhydria,  422 
Hypochondriasis,  493 
Hypoleucocytosis,  239 
Hypothesis,  Ehrlich's,  208 

Welch's,  153 
Hysteria,  493 


Icterus,  434 
Ileus,  441 

Illuminating  gas  poisoning,  248,  512 
Immune  body,  154 
Immunity,  130 

side-chain  theory  of,  151 
Index,  color,  165 


INDEX  OF  SUBJECTS. 


S8i 


Index,  volume,  94,  173 
Infantile  sc  urvy,  429 
Infants,  summer  diarrheas  of,  390 
Infected  wounds,  5  25 
Infection,  latent,  147 
Influenza,  436 

Initial  feeding,  effect  on  blood,  232,  344 
Insolation,  437 
Interstitial  nephritis,  491 
Intestinal  carcinoma,  441 

gangrene,  441 

helminthiasis,  438 

hemorrhage,  408 

inflammation,  300 

obstruction,  441 

perforation,  408 
Iodin  poisoning,  512 
Iodophilia,  226 

experimental,  227 

in  abscess,  361 

in  anemia,  227 

in  appendicitis,  370 

in  cachexias,  227 

in  diabetes  mellitus,  386 

in  enteric  fever,  227 

in  gonorrheal  arthritis,  426 

in  pertussis,  502 

in  pneumonia,  510 

in  pregnancy,  175 

in  puerperal  fever,  529 

in  purpura  hemorrhagica,  227 

in  purulent  lesions,  226 

in  septicemia,  529 

in  syphilis,  535 

in  tuberculosis,  547 
Iron,  effect  on  blood,  163 

in  blood,  161 

in  eosinophiles,  208 
Irritants,  effect  on  blood,  249 
Irritation  forms,  222 
Ischemia,  149 
Isolysis,  154 
Isotonicity,  180 


Jaundice,  434 
Jenner's  stain,  82 
Joffroy's  sign,  276 
Justus'  test,  533 


Kala-azar,  441 
Kidney,  abscess,  363 

carcinoma,  475 

cyst,  327 

inflammation,  489 
stone,  381 
Kra-kra,  413 


Lactation,  effect  on  blood,  175 
Laennec's  cirrhosis,  431 
Laked  blood,  126 

Large  mononuclear  leucocytes,  211 
Latent  infection,  147 
Lead  basophilia,  196 
colic,  371 
poisoning,  512 
Leishman-Donovan  bodies,  442 
Leprosy,  444.  _ 
Leptomeningitis,  487 
Leucocytes,  205 

ameboid  properties,  206 
appearance  in  fresh  blood,  205 
classification,  209 
counting  the,  64,  68,  71,  74 
degeneration,  211 
differential  count  of,  89 

table  of,  223 
fatty  degeneration,  560 
fractured,  38 
granules,  207 
iodin  reaction,  226 
methods  of  counting,  55 
necrobiosis,  211 
normal  number  in  adults,  209 

in  children,  343 
normal  percentages  in  adults,  209 

in  children,  344 
origin  and  development,  224 
perinuclear  basophilia,  228 
phagocytes,  206 
pigmented,  38,  438,  462,  515 
size,  205 
vacuolated,  38 
varieties,  209 
Leucocytolysis,  240 
Leucocytometer,  58 
Leucocytosis,  228 

after  thymectomy,  252 
after  splenectomy,  335 
average  increase,  236 
chloroform,  294 
definition,  228 
differential  changes,  237 
digestion,  231 
drug,  250 
ether,  248 
experimental,  249 
factors,  238 

from  mechanical  and  thermal  influ- 
ences, 234 
functions,  238 
general,  242 

in  general  infectious  diseases,  243 
in  malignant  disease,  245 
in  simple  and  infective  local  inflam- 
mations, 244 
induced,  242 

inflammatory  and  infectious,  242 


582  [NDEX  OF  SUBJECTS. 


Leucocytosis,  influence  of  chemotaxis, 
237 

leucocytic  phase,  240 
leucopenic  phase,  240 
local,  242 

marrow  changes,  241 
of  pregnancy  and  parturition,  233 
of  the  new-born,  229 
pathological,  236 
physiological,  230 
post-hemorrhagic,  246 
post-operative,  244 
terminal,  235 
toxic,  247 
traumatic,  239,  252 
Leucopenia,  260 

experimental,  261 
in  chlorosis,  272 
in  diphtheria,  388 
in  enteric  fever,  406 
in  epilepsy,  261 
in  gastritis,  423 

in  gastro-enteritis  of  infancy,  262 
in  hemorrhagic  diseases,  429 
in  hepatic  cirrhosis,  432 
in  Hodgkin's  disease,  328 
in  infectious  pharyngitis,  262 
in  kala-azar,  443 
in  leukemia,  262 
in  malarial  fever,  469 
in  malignant  endocarditis,  483 
in  measles,  485 
in  paratyphoid  fever,  410 
in  peritonitis,  501 
in  pernicious  anemia,  285 
in  pneumonia,  507 
in  rotheln,  486 
in  secondary  anemia,  298 
in  sepsis,  529 
in  splenic  anemia,  292 
in  sprue,  392 
in  trypanosomiasis,  541 
in  tuberculous  abscess,  549 
in  typhus  fever,  551 
in  yellow  fever,  560 
pathological  262 
physiological,  261 
Leucopenic  phase,  186 
Leukanemia,  290 
Leukemia,  302 
acute,  321 

blood  picture,  321 

clinical  features,  321 

duration,  321 

in  children,  351 

statistics,  321 

transition  from  chronic  forms, 
322 

with  myelogenous  lesions,  304 
frequency  of  different  forms,  304 


Leukemia  in  children,  348 

influence  of  intercurrent  infections, 

322  1 
lymphatic,  3  1  7 

alkalinity,  3 1  7 

appearance  of  fresh  blood,  317 
atypical  lymphocytes,  320 
atypically  stained  erythrocytes, 

318  . 
basophiles,  320 
blood  plaques,  321 
coagulation,  317 
color  index,  317 
deformed  erythrocytes,  318 
diagnosis,  324 
eosinophiles,  320 
erythroblasts,  318 
erythrocytes,  317 
hemoglobin,  317 
leucocytes,  318 
leukoblasts,  319 
lymphocytosis,  319 
lymphogonien,  319 
mast  cells,  320 
myelocytes,  320 
poly  nuclear  neutrophiles,  320 
specific  gravity,  317 
myelogenous,  306 
alkalinity,  307 

appearance  of  fresh  blood,  306 
atypical  myelocytes,  313 

polynuclear  neutrophiles, 
314 

basophiles,  316 

blood  plaques,  317 

Charcot-Leyden  crystals,  307 

coagulation,  307 

color  index,  308 

deformed  erythrocytes,  310 

degenerate  forms  of  leucocytes, 

diagnosis,  323 
dwarf  myelocytes,  313 
neutrophiles,  314 
eosinophilia,  315 
eosinophilic  myelocytes,  316 
erythroblasts,  309 
erythrocytes,  308 
fibrin,  307 

fluctuations  in  hemoglobin  and 
erythrocytes,  308 
in  number  of  leucocytes, 
3ii 

fractured  leucocytes,  314 
granular  basophilia,  310 
hemoglobin,  308 
influence  of  arsenic,  311 

of  x -rays,  312 
karyokinesis,  310 
leucocytes,  310 


INDEX  OF  SUBJECTS. 


583 


Leukemia,  myelogenous,  lymphocytes,  | 

mast  cells,  316 
megaloblasts,  309 
myelocytes,  312 
nuclear  extrusion,  309 
polychromatophilia,  310 
poly  nuclear  neutrophiles,  314  j 
predominance  of  normoblasts, 
3°9 

pvknosis,  310  ; 
relation  of  erythrocyte  and  leu- 
cocyte counts,  308 
remissions,  311 
specific  gravity,  307 
stimulation  forms,  315 
parasitology,  305 
splenectomy  in,  338 
transformation  into  pernicious  ane- 
mia, 304 
transformations  of  type,  304 
varieties,  302 
Leukoblasts,  319 
Light-proof  hemometer  box,  48 
Lipacidemia,  145 

in  acute  yellow  atrophy  of  the  liver, 
365 

in  diabetes  mellitus,  383 
Lipemia,  141 

in  diabetes  mellitus,  383 

in  fractures,  421 

pathological  142 

physiological,  141 
Liquor  sanguinis,  93 
Lithiasis,  pancreatic,  499 
Liver,  abscess,  363 

acute  yellow  atrophy,  365 

carcinoma,  476 

cirrhosis,  430 
Lock-jaw,  535 
Lowenthal's  reaction,  516 
Lowit's  ameba,  305 
Lungs,  malignant  neoplasms  of,  505 
Lupus,  256 
Lymph  scrotum,  421 
Lymphangitis,  421 

Lymphemia,  321.  See  Lymphocytosis. 
Lymphocytes,  large,  210 

small,  211 
Lymphocytosis,  252 

absolute,  252 

after  splenectomy,  336 

cachectic,  253 

definition,  252 

differential  changes,  252 

drug,  254 

factors,  253 

in  acromegaly,  364 

in  actinomycosis,  364 

in  acute  infections,  254 


iphocytosis  in  acute  leukemia,  321 
in   anemia  infantum  pseudoleu- 
kemia, 355 
in  Addison's  disease,  366 
in  adenitis,  254 
in  adenoids,  375 
in  Asiatic  cholera,  374 
in  beri-beri,  492 
in  bronchitis,  375 
in  bubonic  plague,  378 
in  carcinoma,  478,  481 
in  children,  344 
in  chloroma,  379 
in  chlorosis,  272 
in  constitutio  lymphatica,  254 
in  convulsions,  495 
in  diphtheria,  389 
in  enteric  fever,  408 
in  epithelial  neoplasms,  481 
in  exophthalmic  goitre,  411 
in  filariasis,  420 
in  gastritis,  423  _ 
in  gastro -enteritis,  353 
in  Hodgkin's  disease,  328 
in  kala-azar,  443 
in  lymphatic  leukemia,  319 
in  malarial  fever,  470 
in  malignant  disease,  478,  480 
in  Malta  fever,  484 
in  measles,  486 
in  meningitis,  488 
in  osteomalacia,  499 
in  paresis,  495 
in  pernicious  anemia,  286 

in  pertussis,  502 

in  pneumonia,  510 

in  protozoan  infections,  254 

in  purpura,  430 

in  rachitis,  353 

in  rheumatic  fever,  520 

in  rotheln,  486 

in  sarcoma,  480 

in  scarlet  fever,  524 

in  scurvy,  430 

in  secondary  anemia,  298 

in  splenic  anemia,  293 
tumors,  254 

in  sprue,  392 

in  syphilis,  535 

in  thyroid  tumors,  254 

in  tracheobronchial  adenitis,  375 

in  tropical  hematochyluria,  254 

in  trypanosomiasis,  541 

in  tuberculosis,  547 

in  varicella,  555 

in  variola,  557 

of  infancy,  344 

post-hemorrhagic,  301 

relative,  252 

terminal,  254 


584  INDKX  OK 

Lymphogonien,  319 
Lymphoma,  332 


Macrocytes,  182 
Macrophages,  239 
Making  the  puncture,  34 
Malarial  anemia,  460 
cachexia,  468 
fever,  445 

action  of  quinin,  446 
amebula,  449 
anemia,  466 
blood  plaques,  471 
diagnosis,  471 
erythrocytes,  466 
hemoglobin,  466 
incidence,  448 
leucocytes,  469 
parasite,  445 

crescentic  forms,  460 
degenerate    forms,  452, 

457;  461 
development  in  man,  445 

in  mosquito,  446 
differential  table,  463 
(     disc  forms,  458 

estivo-autumnal,  457 
extracellular  pigmented 

forms,  452,  456,  460 
flagellate  forms,  453,  457, 
461 

gamete  forms,  452,  456, 
461 

infection    with  multiple 

groups,  448,  454 
intracellular  hyaline 

forms,  449,  454,  457 
intracellular  pigmented 

forms,  450,  455;  45 8 
leucocytes,  462 
ovoid  bodies,  460 
quartan,  454 
ring  forms,  458 
segmenting    forms,  451, 

456,  459 
spherical  bodies,  460 
sporocytes,  451 
staining,  464 
tertian,  448 

vacuolized    forms,  454, 
457;  461 
phagocytosis,  462 
technic  of  examination,  464 
hematuria,  467,  470 
spleen,  338 
Male  chlorosis,  275 
Malignant  disease,  472 
-endocarditis,  482 
jaundice,  365 


SUBJECTS. 

Mallory's  protozoon,  522 
Malta  fever,  484 
Mania,  496 

Maragliano's  necrosis,  176 

Marmorek's  method,  518 

Massage,  effect  on  blood,  176 

Mast  cell  granules,  207 
cells,  219 

in  Addison's  disease,  366 

in  appendicitis,  259 

in  Asiatic  cholera,  374 

in  carcinoma,  478 

in  chlorosis,  258 

in  filariasis,  420 

in  gonorrhea,  258 

in  infantile  anemias,  346 

in  lymphatic  leukemia,  320 

in  mycosis  fungoides,  258 

in  myelogenous  leukemia,  318 

in  plumbism,  259 

in  septic  bone  disease,  258 

in  skin  diseases,  258 

in  splenic  anemia,  293 

in  trichiniasis,  538 

in  trypanosomiasis,  541 

Mastitis,  244 

Masturbation,  494 

Measles,  485 

Megaloblastic  blood  picture,  282 
Megaloblasts,  189 
Megalocytes,  182 
Melancholia,  494 
Melanemia,  107 

in  Addison's  disease,  366 

in  insolation,  438 

in  malarial  fever,  462 

in  relapsing  fever,  515 
Meningitis,  486 

cerebro-spinal,  488 

tuberculous,  487 
Menstruation,  effect   on   blood,  164, 

175 

Mental  diseases,  492 
Mercury,  effect  on  blood,  533,  535 
Mesoblasts,  192 
Methemoglobin,  161 

spectrum  of,  168 

tests  for,  167 
Methemoglobinemia,  167 

from  drugs,  167 

from  influence  of  radium  rays,  167 

in  Addison's  disease,  366 

in  chloroform  narcosis,  249 

in  poisoning,  511 

in  purpura  hemorrhagica,  427 
Methods,  fixation,  79 

non-clinical,  122 

of  examination,  33 

of  staining,  81 
Metschnikoff's  theory,  230 


INDEX  OF 


Microblasts,  192 
Microcytcs,  182 
Microphages,  239 

Microspectroscope,  Sorby-Beck,  107 
Mikulicz's  dictum,  164 
Milian's  method,  100 
Mitral  lesions,  447 
Monochromatophilia,  186 
Mononuclear  neutrophils,  222 
Mononucleosis,  252.     See  Lymphocy- 
tosis. 

Mosquito,  dengue,  382 

development  of   Filaria  nocturna 
in,  41S 

of  malarial  parasite  in,  446 
yellow  fever,  559 
Mucinoblasts,  221 
Multiple  neuritis,  492 

periostitis,  326 
Muscular  exercise,  effect  on  blood,  176, 
234 

Myelemia,  259 
Myelocytes,  217 

atypical  forms  in  leukemia,  313 

dwarf,  222 

eosinophilic,  219 

in  abscess,  363 

in  actinomycosis,  344 

in  Addison's  disease,  366 

in  anemia  of  children,  346 

infantum  pseudo-leukemica, 
355 

in  bubonic  plague,  378 
in  burns,  378 
*  in  carcinoma,  478 
in  chloroma,  379 
in  chlorosis,  274 
in  convulsions,  495 
in  diabetes  mellitus,  386 
in  diphtheria,  389 
in  enteric  fever,  409 
in  epilepsy,  497 
in  erysipelas,  411 
in  gastro-enteritis,  353 
in  gout,  427 
in  herpes  zoster,  434 
in  Hodgkin's  disease,  330 
in  infantile  enteric  fever,  354 

scurvy,  430 

syphilis,  352 

tuberculosis,  353 
in  lymphatic  leukemia,  320 
in  malarial  fever,  471 
in  myelogenous  leukemia,  312 
in  myxedema,  489 
in  osteomalacia,  499 
in  osteosarcoma,  480 
in  pernicious  anemia,  274 
in  phthisis,  547 
in  pneumonia,  510 


SUB  J  KITS.  585 

Myelocytes  in  posthemorrhagic  leuco- 
cytosis,  248 
in  rachitis,  353 
in  sarcoma,  480 
in  scarlet  fever,  524 
in  secondary  anemia,  298 
in  sepsis,  529 
in  splenic  anemia,  293 
in  sprue,  392 
in  syphilis,  535 
in  trichiniasis,  536 
in  tuberculosis,  547 
in  varicella,  555 
in  variola,  557 

in  von  Jaksch's  periostitis,  259 

in  yellow  fever,  560 
Myxedema,  488 
Myxococcidium  stegomyiae,  559 


Necrobiosis,  211 
Necrosis,  Maragliano's,  185 
Needle  for  blood  culturing,  110 
Negro  lethargy,  539 
Nephrectomy,  492 
Nephritis,  489 
Nervous  diseases,  492 
Neuralgia,  492 

ovarian,  371 
Neurasthenia,  493 

gastric,  422 

sexual,  494 
Neuritis,  492 
Neuroses,  functional,  493 
Neutral  dyes,  76 
Neutrophile  granules,  208 
Neutrophiles,  mononuclear,  222 

polynuclear,  214 
Neutrophilic  pseudo-lymphocytes,  222 
Newton's  rings,  62 
Nikiforoff's  method  of  fixation,  80 
Nitrobenzene  poisoning,  512 
Nitroglycerin  poisoning,  512 
Normoblasts,  187 
Nuclear  stains,  76 
Nucleated  erythrocytes,  187 
Nucleolation  of  lymphocytes,  320 


Obermeier's  spirillum,  514 

Obesity,  498 

Objects  of  staining,  75 

Obstruction,  intestinal,  441 

Obstructive  jaundice,  coagulation  in, 

38°>  434 
Ocular  diaphragm,  65 
Odor  and  viscosity  of  blood,  127 
Oligemia,  149 
Oligochromemia,  163 
Oligocythemia,  148 


586 


[NDEX  OF  SUBJECTS. 


{ Mixer's  hemot  ylometer,  7  1 

hemoglobinometer,  40. 
Opium  poisoning,  512 
Opsonin,  239 
Osmic  acid  fixation,  8  1 
Osteomalacia,  498 
Osteomyelitis,  525 

tuberculous,  546 
Osteosarcoma,  259,  480 
Otitis  media,  244 

Oval-shaped  erythrocytes,  115,  184 
in  epidemic  dropsy,  282 
in  pernicious  anemia,  281 
in  purpura  hemorrhagica,  281 
Ovarian  abscess,  370 
cyst,  371 
neuralgia,  371 
Ovaritis,  244 
Oven  for  fixation,  79 
Oxyhemoglobin,  161 
spectrum  of,  168 
Oxyuris  vermicularis,  441 


Pachymeningitis,  487 
Pancreatitis,  499 
Panoptic  staining,  81 
Paralysis,  family  periodic,  497 
Paratyphoid  fever,  394,  404 
Parenchymatous  nephritis,  490 
Paresis,  494 

Pathological  basophilia,  258 

eosinophilia,  256 

leucocytosis,  236 

leucopenia,  262 

lymphocytosis,  254 
Pellagra,  244 
Pelvic  abscess,  370 
Pemphigus,  244 
Pericardial  effusion,  500 
Perinuclear  basophilia,  228 
Periostitis,  multiple,  326 
Peritonitis,  500 

appendicular,  368 

hysterical,  501 

septic,  500 

serous,  500 

tuberculous,  546,  549 
Pernicious  anemia,  276 
alkalinity,  278 

appearance  of  fresh  blood,  276 
blood  plaques,  287 
blood  volume,  276 
coagulation,  278 
color  index,  279 
diagnosis,  288 
dry  residue,  276 
Eichhorst's  corpuscles,  281 
eosinophiles,  286 
erythroblasts,  282 


Pernicious  anemia,  erythrocytes,  278 
fibrin,  278 

fluctuations    in    number  of 

erythrocytes,  280 
granular  basophilia,  285 
hemoglobin,  278 
horseshoe-shaped  cells,  281 
in  children,  347 
isotonicity,  181 
leucocytes,  285 
megaloblasts,  282 
megalocytes,  280 
mesoblasts,  283 
microblasts,  285 
myelocytes,  287 
nuclear  extrusion,  284 
oligemia,  276 
oval-shaped  cells,  281 
phantom  corpuscles,  277 
poikilocytosis,  281 
polychromatophilia,  285 
polynuclear  neutrophiles,  286 
predominance  of  megaloblasts, 

282 

relative  lymphocytosis,  286 
rouleaux  formation,  277 
specific  gravity,  278 
symptoms,  288 
syphilitic,  533 

transformation  into  leukemia, 
290 

Pertussis,  502 

Pfeiffer's  phenomenon,  112 
Phagocytosis,  206,  238 

in  malarial  fever,  462 

in  relapsing  fever,  517 
Phantom  corpuscles,  184 

tumor,  502 
Phenacetin  poisoning,  512 
Phlebitis,  244 
Phosphorus  poisoning,  512 
Physiological  eosinophilia,  256 

leucocytosis,  230 

leucopenia,  261 

lymphocytosis,  253 
Pigmented  leucocytes  in  insolation,  438 
in  malarial  fever,  462 
in  relapsing  fever,  515 
Pinocytosis,  206 
Pipette,  Durham's,  68 

Gowers',  52 

Oliver's,  50 

Thoma-Zeiss,  57 

Von  Fleischl's,  43 
Piroplasma,  443,  531,  551 
Plague,  bubonic,  376 
Plasma  stains,  76 
Plasmodium  malarise,  445 
Plasmotrophic  action,  439 
Plethora,  138 


!N1>K\  OF  SUBJECTS. 


587 


Plethora  in  chlorosis,  267 
in  hemophilia,  427 
in  obesity,  4()8 

in  valvular  heart  disease,  553 
Pleura,  malignant  neoplasms  of,  505 
Pleurisy,  purulent,  504 

serous,  503 
Plimmer's  bodies,  473 
Plurabie  neuritis,  492 
Plumbism,  acute,  196,  512 
Pneumonia,  catarrhal,  508 
eroupous,  505  . 

bacteriology,  505 
blood  plaques,  510 
diagnosis,  511 

effect  of  aleuron  and  digitalis, 
5°9 

antipneumococcus  serum, 
5°9 

antipyretics  and  cold,  510 
erythrocytes,  507 
hemoglobin,  507 
hyperinosis,  505 
induced  leucocytosis,  509 
iodin  reaction,  510 
leucocytes,  507 
lymphocytosis,  510 
serum  test,  505 
specific  gravity,  505 
Poggi's  corpuscles,  185 
Poikilocytes,  183 
Poisoning,  511 
Polychromatophilia,  186 
Polycythemia,  197 
after  burns,  378 
after  exercise,  176 
after  purgation,  392 
after  transfusion,  301 
after  urinary  crises,  198 
cyanotic,  381 

during  blood  regeneration,  301 
digestion,  177 
menstruation,  175 
from   administration   of  lympho- 

gogues  and  emetics,  198 
from  physiological  causes,  198 
in  acute   yellow   atrophy   of  the 

liver,  365 
in  ascites,  431 
in  Asiatic  cholera,  373 
in  asthma,  374 
in  bubonic  plague,  377 
in  convulsions,  495 
in  diabetes  mellitus,  385 
in  diarrhea,  390 
in  diphtheria,  387 
in  emphysema,  374 
in  erythromelalgia,  493 
in  fever,  412 

in  gastric  and  esophageal  card 
noma,  474 


Polycythemia  in  gastric  and  esophageal 
ulcer,  423 
in  gastritis,  421 
in  gout,  427 

in  hepatic  cirrhosis,  43  i 
in  icterus,  436 

in  illuminating-gas  poisoning,  512 
in  insolation,  437 
in  leprosy,  444 
in  malarial  fever,  466 
in  nephritis,  491 
in  Osier's  disease,  381 
in  phosphorus  poisoning,  512 
in  pleural  effusion,  503 
in  pneumonia,  507 
in  the  new-born,  174 
in  trichiniasis,  536 
in  tuberculosis,  545 
in  valvular  heart  disease,  553 
in  variola,  556 
of  high  altitudes,  178 
Polyemia,  138 

Polynuclear  neutrophiles,  214 
Ponfick's  corpuscles,  185 
Post-hemorrhagic  anemia,  299 
blood  crises,  302 
plaques,  301 
color  index,  302 
erythroblasts,  302 
erythrocytes,  299 
etiology,  299 
fatality,  300 
hemoglobin,  240,  299 
hydropic  erythrocytes,  302 
immediate  effects  of  blood  loss, 
299 

leucocytes,  300 
leucocytosis,  246 
lymphocytosis,  247 
microcytes,  302 
oligemia,  299 
polychromatophilia,  302 
polycythemia,  302 
rapidity  of  hemoglobin  gain, 
302 

regeneration,  301 
saline  solution,  effect  of,  301 
Post-operative  leucocytosis,  244 
Potassium  chlorate  poisoning,  512 

permanganate  poisoning,  513 
Pott's  disease,  546,  548 
Preagonal  leucocytosis,  235 
Precipitins,  157 
Pregnancy,  131,  135 

ectopic,  370 
Preparing  the  films,  76 

the  slide,  35 
Prince's  stain,  85 
Prison  pallor,  149 
Protozoa  in  beri-beri,  492 

in  carcinoma,  473 


588  INDEX  OF 

Protozoa  in  dengue,  382 

in  kala-azar,  441 

in  leukemia,  305 

in  measles,  485 

in  scarlet  fever,  522 

in  spotted  fever,  531 

in  trypanosomiasis,  538 

in  varicella,  554 

in  variola,  555 

in  yellow  fever,  558 
Prurigo,  256 
Pseudo-anemia,  149 

bacilli,  183 

chlorosis,  199 

lymphocytes,  neutrophilic,  222 
Psoriasis,  256 
Ptomain  poisoning,  513 
Puerperal  fever,  525 
Purges,  effects  on  blood,  392 
Purpura,  427 
Purulent  lesions,  361 
Pyelonephritis,  244 
Pyemia,  525 
Pyknosis,  310 
Pyonephrosis,  244 
Pyosalpinx,  370 
Pyrodin  poisoning,  513 
Pyrogallol  poisoning,  513 

Quantity  of  blood,  125 
Quinsy,  536 
Quotient,  blood,  165 

Rabies,  513 

Radium  rays,  effect  on  blood,  167 
Ranvier's  solution,  114 
Raspberry-jelly  clots,  307, 
Ratio  of  erythrocytes  to  leucocytes,  205 

to  plaques,  90. 
Reaction.   See  Test.  Arloing  and  Cour- 
mont's,  542 
Bordet's,  117 
LowenthaPs,  516 
of  blood,  128 

pathological  variations,  130 
physiological  variations,  129 
tests  for,  96 
Pfeiffer's,  112 
Widal's,  112 
Receptors,  152 
Rectum,  carcinoma  of,  476 
Red  blood  corpuscles,  169.    See  Eryth- 
rocytes. 
Reichert's  method,  161 
Reizungsformen,  222 
Relapsing  fever,  514 

diagnosis,  517 
erythrocytes,  516 
hemoglobin,  516 


SUBJECTS. 

Relapsing  fever,  leucocytes,  51.6 

.  LowenthaPs  reaction,  516 

melanin,  515 

parasitology,  514 

phagocytosis,  517 
Remissions  in  myelogenous  leukemia , 

:  311 

in  pernicious  anemia,  280 
Renal  colic,  381 

disease,  freezing  point  of  blood,  103 
Revulsives,  effect  on  blood,  249 
Rheumatic  fever,  518 

alkalinity,  518 

bacteriology,  518 

coagulation,  518 

color  index,  519 

diagnosis,  520 

erythrocytes,  519 

fibrin,  518 

hemoglobin,  519 

leucocytes,  520 
Rheumatism,  chronic,  519 

muscular,  501 
Ring  bodies,  194 
Rollet,  stroma  of,  170 
Ross'  method,  77 
Rotheln,  169 
Rouleaux  formation,  169 
Row's  test,  377 
Rupture  of  the  spleen,  338 
Russell's  bodies,  473 

Saline  purges,  effect  on  blood,  392 
Salts  of  blood,  126 
Sanarelli's  bacillus,  558 
Sapremia,  525 
Sarcoma,  478 

coagulation,  478 
cytodiagnosis,  478 
deformed  erythrocytes,  479 
diagnosis,  480 
erythroblasts,  479 
erythrocytes,  478 
fibrin,  478 
hemoglobin,  478 
leucocytes,  479 
specific  gravity,  478 
Scarlet  fever,  521 

bacteriology,  522 
blood  plaques,  524 
coagulation,  521 
diagnosis,  525 
erythrocytes,  522 
fibrin,  521 
hemoglobin,  522 
leucocytes,  523 
protozoa,  522 
specific  gravity,  521 
Schistocytosis,  185 
Schiiffner's  granules,  196 


1NDHX  OF  SUBJECTS. 


589 


Scleroderma,  256 
Scorpion  poisoning,  5  '  0 
Scrofula,  545 
Scrotum,  lymph,  421  ' 
Scurvy,  427 

infantile,  429 
Secondary  anemia,  296 
alkalinity,  296 

appearance  of  fresh  blood,  296 

average  hemoglobin  and  eryth- 
rocyte losses,  297 

blood  plaques,  298 

coagulation,  296 

color  index,  297 

deformed  erythrocytes,  297 

diagnosis,  298 

eosinophiles,  298 

erythroblasts,  298 

erythrocytes,  296 

granular  basophilia,  298 

hemoglobin,  296 

leucocytes,  298 

myelocytes,  298 

pallor  of  erythrocytes,  297 

poikilocytosis,  297 

polychromatophilia,  297 

poly  nuclear  neutrophiles,  298 

relative  lymphocytosis,  298 

specific  gravity,  296 
Septic  arthritis,  525 
Septicemia  and  pyemia,  525 

bacteriology,  526 

color  index,  528 

diagnosis,  530 

erythrocytes,  527 

fibrin,  525 

hemoglobin,  527 

leucocytes,  529 

serum  reaction,  525 
Serous  plethora,  139.    See  Hydremia. 
Serum  reaction,  determination  of,  112 

in  Asiatic  cholera,  372 

in  bubonic  plague,  377 

in  children,  354 

in  colon  infections,  496,  525 

in  dysentery,  391 

in  enteric  fever,  396 

in  glanders,  425 

in  icterus,  403 

in  kala-azar,  444 

in  leprosy,  444 

in  Malta  fever,  484 

in  non-typhoid  conditions,  403 

in  paratyphoid  fever,  404 

in   pneumococcus  infections, 
526 

in  pneumonia,  505 

in  relapsing  fever,  511 

in  septicemia,  525 

in  streptococcus  infections,  525 


Serum  reaction  in  tuberculosis,  542 

in  Weil's  disease,  403 
Sexual  neurasthenia,  494 
Shadow  corpuscles,  184 
Sherrington's  solution,  56 
Shiga's  bacillus,  391 
Shingles,  434 

Side-chain  theory,  Ehrlich's,  151 
Sign,  Joffroy's,  217 
Sleeping  sickness,  539 
Slide,  preparing  the,  315 
Small  lymphocytes,  210 
Small-pox,  555 
Snake  poisoning,  513 
Sodium  nitrite  poisoning,  513 
Solution,  Brodie  and  Russell's,  91 

Denige's,  145 

Determann's,  91 

Hayem's,  56 

isotonic,  180 

Ranvier's,  114 

saline,  after  hemorrhage,  301 
Sherrington's,  56 
Toisson's,  56 
Sorby-Beck  microspectroscope,  107 
Sorby's  tubular  cell,  108 
Specific  gravity,  132 

estimation  of,  94 
in  Asiatic  cholera,  372 
in  carcinoma,  472 
in  children,  342 
in  chlorosis,  268 
in  diabetes  mellitus,  385 
in  Hodgkin's  disease,  327 
in  icterus,  434 
in  lymphatic  leukemia,  317 
in  myelogenous  leukemia,  307 
in  nephritis,  489 
in  pernicious  anemia,  2  78 
in  phthisis,  545 
in  pneumonia,  505 
in  purpura  hemorrhagica,  427 
in  sarcoma,  478 
in  scarlet  fever,  521 
in  secondary  anemia,  296 
in  the  fetus,  341 
in  the  new-born,  342 
in  valvular  heart  disease,^ 5 3 
in  yellow  fever,  559 
normal  range,  132 
pathological  variations,  132 
table  of  hemoglobin  equiva- 
lents, 133 
Spectra,  blood,  168 
Spectroscopical  examination,  107 
Spirilla  in  Malta  fever,  484 
Spirillum  of  Obermeier,  514 
Spleen,  hemolytic  action,  225 
inflammation,  244 
malarial,  338 


59°  INDEX  OF 

Spleen,  neoplasms,  327 
rupture,  338 
tropical,  442 
wandering,  338 
Splenectomy,  333 
Splenic  anemia,  291 

appearance  of  fresh  blood,  291 
blood  plaques,  293 
color  index,  291 
diagnosis,  293 
eosinophiles,  293 
erythroblasts,  292 
erythrocytes,  291 
hemoglobin,  291 
leucocytes,  292 
mast  cells,  293  ' 
megaloblasts,  292 
megalocytosis,  292 
myelocytes,  293 
poikilocytosis,  292 
polychromatophilia,  292 
polynuclear  neutrophiles,  293 
relative  lymphocytosis,  293 
symptoms,  294  i 
Splenitis,  244 
Splenolymph  glands,  172 
Splenomegaly,  295 

tropical,  442 
Sporoblasts,  447 
Sporozoids,  447 
Spot  culturing,  395 
Spotted  (Montana)  fever,  531 

(typhus)  fever,  550 
Sprue,  392 
Stain,  Delafield's,  87 
Ehrlich's  triacid,  83 
Ehrlich-Weigert,  112 
eosin  and  hematoxylin,  87 

methylene-blue,  86 
Goldberger  and  Weiss',  226 
Goldhorn's,  88 
Hewes',  85 
Jenner's,  82 
Leishman's,  82 
Loffler's,  85 

polychrome  methylene-blue,  88 

Prince's,  85 

Romano wsky,  82 

thionin,  87 

Wright's,  82 
Stained  specimen,  examination  of  the,  75 
Staining,  methods  of,  81 

bacteria,  1 1 1 

basophilic  erythrocytes,  194 
cellular  elements,  82 
diabetic  blood,  385 
double,  87 
filaria,  419 

Hemamceba  leukemia?,  305 
Hemamceba  malariae,  464 


SUBJECTS. 

Staining  iodophile  cells,  175,  226 

Neusser's  granules,  228 

objects  of,  75 

panoptic,  81 

ring  bodies,  194 

Schuffner's  granules,  469 

Spirillum  obermeieri,  515 

triple,  83 

trypanosoma,  540 
Stasis,  effect  on  blood,  553 
Stegomyia  fasciata,  558 
Still's  disease,  326 
Stimulation  forms,  222 
Stomach,  carcinoma,  476,  481 

dilatation,  422 

inflammation,  421 

ulcer,  423 
Stroma  of  Rollet,  170 
Strong  and  Seligmann's  method,  73 
Strongyloides  intestinalis,  441 
Sugar  in  the  blood,  143 

after  pancreatectomy,  143 
in  carcinoma,  472 
in  diabetes  mellitus,  383 
test  for,  143 
Sunstroke,  437 

Sweating,  effect  on  blood,  198,  234 
Syphilis,  532 

bacteriology,  532 

diagnosis,  535 

effect  of  treatment,  533 

erythrocytes,  532 

hemoglobin,  532 

Justus'  test,  533 

leucocytes,  534 

Tallquist's  hemoglobinometer,  54 
Tansy  poisoning,  513 
Tape  worms,  440 
Teichmann's  crystals,  162 

test,  115 
Terminal  leucocytosis,  235 
Test,  biological,  117.    See  Reaction. 

Bordet's,  117 

Bremer's,  384 

Ficker-Reudiger,  401 

for  acetone,  145 

for  alkalinity,  96 

for  bile,  145 

for  carbon  monoxid  hemoglobin,  169 

for  fat,  142 

for  fatty  acids,  146 

for  glycogen,  226 

for  hemin,  115 

for  hemoglobin,  40 

for  hemoglobinemia,  167 

for  human  blood,  114 

for  methemoglobin,  167 

for  sugar,  108,  143 

for  uric  acid,  144 


INDEX  OF 

Test  Garrod's,  144 

guaiacum,  116 

hanging-drop,  122 

Justus',  533 

Lowenthal's,  516 

Marx  and  Ehrnrooth's,  122 

medico-legal,  114 

Row's,  377 

Schaffer's,  175 

Teichmann's,  115 

Van  Deen's,  116 

Widal's,  112 

Williamson's,  383 

Wolff's,  402 
Tetanus,  535 
Tetany,  498 
Theory,  side-chain,  151 
Thermotaxis,  238 
Thionin  stain,  87 
Thoma-Zeiss  hemocytometer,  57 
Thrombosis,  393 

Thymectomy,  leucocytosis  after,  252 

Thyroidization,  489 

Tick  fever,  531 

Toadstool  poisoning,  513 

Toisson's  solution,  5,6 

Toluene  poisoning,  513 

Toluylendiamin  poisoning,  513 

Tonsillitis,  535 

Total  necrosis,  185 

Toxic  leucocytosis,  247 

Toxins  152 

Toxoids,  153 

Toxones,  153 

Toxophores,  152 

Transitional  forms,  213 

Triacid  stain,  83 

Trichiniasis,  536 

Trichocephalus  dispar,  438 

Tropical  anemia,  149 

splenomegaly,  442 
Trypanosoma  gambiense,  539 
Trypanosomiasis,  538 
Tsetse-fly,  539 
Tuberculosis,  541 

bacteriology,  542 

diagnosis,  550 

erythrocytes,  544 

forms  of  anemia,  545 

genito-urinary,  546,  549 

glandular,  546,  549 

hemoglobin,  544 

hip-joint,  546,  548 

iodophilia,  547 

leucocytes,  546 

meningeal,  546,  549 

osseous,  546,  548 

peritoneal,  546,  549 

pleural,  546,  549 

polycythemia,  545 


SUBJECTS.  591 

Tuberculosis,  pulmonary,  545,  547 

secondary  infections,  545,  547 

serum  reaction,  542 

vertebral,  546,  548 
Tuberculous  meningitis,  487 
Tubular  cell,  Sorby's,  108 
Tumor,  brain,  493 

phantom,  502 
Turpentine  poisoning,  513 
Typhoid  fever,  393.    See  Enteric  Fever. 
Typhus  fever,  550 

Ulcer,  duodenal,  425 

gastric,  423 
Uncinariasis,  440 
Uniceptors,  152 
Uremia,  492 

freezing  point  of  blood,  103 
Uric  acid  in  gout,  426 

relation  to  leucocytolysis,  263 
test  for,  144 
Uricacidemia,  144 
Urinary  crises,  effects  on  blood,  198 
Urticaria,  256 
Uskow's  theory,  224 
Uterus,  carcinoma  of,  476 

Vaccination,  552 
Valee's  law,  117 
Valeur  globulaire,  165 
Valvular  heart  disease,  552 
Varicella,  554 
Variola,  555 
Varioloid,  557 
Vegetarians,  177 
Violet  of  Hoyer,  87 
Viscosity  of  blood,  127 

value,  128 
Volume  index,  94,  173 

of  corpuscles  and  plasma,  estima- 
tion of,  91 
Vomiting,  effect  on  blood,  198 
Von  Fleischl's  hemometer,  43 
Von  Jaksch's  anemia,  354 

Waldstein's  smearing  slip,  78 
Wandering  spleen,  338 
Welch's  hypothesis,  153 
White  blood  corpuscles,  205 .  See  Leuco- 
cytes. 

Whooping-cough,  502 
Widal's  test,  112 
Williamson's  test,  383 
Wright's  coagulometer,  101 
stain,  82 

Yellow  fever,  558 

Zappert  counting  chamber,  59 
Zollikofer's  method,  226 
Zygotes,  447 
Zymophores,  155 


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